title: Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL.
abstract: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals.
  
  
  
  We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography.
  
  
  
  We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation.
  
  
  
  The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nozaki
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kato
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Nihonmatsu
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Saito
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Mizuta
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Noda
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Koike
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Miyazaki
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Muichi
authors.initials: M
authors.lastname: Kaito
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ito
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Makino
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Koyama
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiga
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Uemura
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sekine
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Ayuka
authors.initials: A
authors.lastname: Murakami
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Suzuko
authors.initials: S
authors.lastname: Moritani
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Kenju
authors.initials: K
authors.lastname: Hara
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Yokoseki
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Endo
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Momotsu
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: From the Department of Medical Technology, School of Health Sciences, Faculty of Medicine (H.N.), Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute (T.K., A.Y., O.O.), Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute (M. Nihonmatsu, Y. Saito, A.K., A.S., M.U., Y. Sekine, M. Nishizawa), Department of Regenerative and Transplant Medicine, Division of Orthopedic Surgery (N.E.), and Department of Molecular Genetics, Bioresource Science Branch, Brain Research Institute (R. Kuwano), Niigata University, Niigata City; Department of Neurology (I.M., T. Mizuno), Kyoto Prefectural University of Medicine; Department of Neurology (T.N.), Ichinomiya Municipal Hospital, Aichi; Department of Neurology (R. Koike), Nishi-Niigata Chuo National Hospital, Niigata; Department of Neurology (K.M.), Shiseikai-Daini Hospital, Tokyo; Department of Neurology (M.K.), Kanazawa Medical University, Ishikawa; Department of Neurology (S.I.), Chiba University; Department of Neurology (M.M.), Nantan General Hospital, Kyoto; Departments of Neurology (A.M.) and Advanced Diagnosis (S.M.), Nagoya Medical Center, Aichi; Department of Neurology (K.H.), Japanese Red Cross Akita Hospital; Department of Internal Medicine (T. Momotsu), Sado General Hospital, Niigata; and Institute for Medical Science of Aging (M.Y.), Aichi Medical University, Japan. onodera@bri.niigata-u.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
mesh_terms: D000505:Alopecia / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology; D002544:Cerebral Infarction / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D002850:Chromatography, Gel; D019281:Dimerization; D005190:Family; D006579:Heterozygote; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D056784:Leukoencephalopathies / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D013122:Spinal Diseases / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
chemical_list: D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases