title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
abstract: Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders.
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Rocio
authors.initials: R
authors.lastname: Acuna-Hidalgo
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Denny
authors.initials: D
authors.lastname: Schanze
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.
authors.forename: Mohamad Hasan
authors.initials: MH
authors.lastname: Kariminejad
authors.affiliation: Center for Fetal Medicine, Department of Obstetrics and Gynecology, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Conner
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Freyer
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Wredenberg
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, 45122 Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, 23562 Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey.
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Pediatrics Genetics Division, Pediatrics Department, Marmara University Medical Faculty, 34668 Istanbul, Turkey.
authors.forename: Nursel
authors.initials: N
authors.lastname: Elcioglu
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.
authors.forename: Siavash
authors.initials: S
authors.lastname: Ghaderi-Sohi
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.
authors.forename: Payman
authors.initials: P
authors.lastname: Goodarzi
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Setayesh
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: van de Vorst
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: Steehouwer
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Division of Human Genetics, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Krabichler
authors.affiliation: Department of Pediatrics, University of California, San Francisco, Fresno, CA 93701, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Curry
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H8L1, Canada.
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: MacKenzie
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H8L1, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Division of Human Genetics, Innsbruck Medical University, 6020 Innsbruck, Austria; Department of Pediatrics I, Innsbruck Medical University, 6020 Innsbruck, Austria. Electronic address: andreas.janecke@i-med.ac.at.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: alexander.hoischen@radboudumc.nl.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D001927:Brain Diseases / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D005190:Family; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D050543:Phosphoglycerate Dehydrogenase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000096:biosynthesis* / Q000737:chemistry; D000637:Transaminases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*
chemical_list: D012694:Serine; D050543:Phosphoglycerate Dehydrogenase; D000637:Transaminases; C022393:phosphoserine aminotransferase; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase