title: A missense mutation in domain III in HSPG2 in Schwartz-Jampel syndrome compromises secretion of perlecan into the extracellular space.
abstract: Schwartz-Jampel syndrome (SJS) type 1 is characterized by short stature, myotonia, and chondrodysplasia, and is caused by partial loss-of-function mutations in HSPG2 encoding perlecan. Six missense mutations have been reported in SJS to date and only one has been characterized using a recombinant protein. We report an 11-year-old Japanese boy with SJS, who shows "rigid" walking with less flexion of knees/ankles and protruded mouth. His intelligence is normal. We identified by whole genome resequencing a heterozygous missense p.Leu1088Pro in domain III-2 and a heterozygous nonsense p.Gln3061Ter in domain IV of perlecan. Expression studies revealed that p.Leu1088Pro markedly reduces the cellular expression of domain III-2 and almost nullifies its secretion into the culture medium. As five of the seven missense mutations in SJS affect domain III of perlecan, domain III is likely to be essential for secretion of perlecan into the extracellular space.
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Ito
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Nakata
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Noguchi
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Bisei
authors.initials: B
authors.lastname: Ohkawara
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Goto
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan; Department of Pediatrics, Jichi Medical School, Shimotsuke, Tochigi, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.affiliation: Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Nonaka
authors.affiliation: Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Arikawa-Hirasawa
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. Electronic address: ohnok@med.nagoya-u.ac.jp.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
mesh_terms: D044466:Asian People; D002648:Child; D005110:Extracellular Space; D057809:HEK293 Cells; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007564:Japan; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism
chemical_list: D019812:Heparan Sulfate Proteoglycans; C071927:perlecan
keywords: Perlecan; Schwartz–Jampel syndrome; Whole genome resequencing analysis