Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway

Am J Hum Genet. 2014 Sep 4;95(3):285-93. doi: 10.1016/j.ajhg.2014.07.012.

Rocio Acuna-Hidalgo ¹, Denny Schanze ², Ariana Kariminejad ³, Ann Nordgren ⁴, Mohamad Hasan Kariminejad ³, Peter Conner ⁵, Giedre Grigelioniene ⁴, Daniel Nilsson ⁴, Magnus Nordenskjöld ⁴, Anna Wedell ⁶, Christoph Freyer ⁷, Anna Wredenberg ⁷, Dagmar Wieczorek ⁸, Gabriele Gillessen-Kaesbach ⁹, Hülya Kayserili ¹⁰, Nursel Elcioglu ¹¹, Siavash Ghaderi-Sohi ³, Payman Goodarzi ³, Hamidreza Setayesh ³, Maartje van de Vorst ¹, Marloes Steehouwer ¹, Rolph Pfundt ¹, Birgit Krabichler ¹², Cynthia Curry ¹³, Malcolm G MacKenzie ¹⁴, Kym M Boycott ¹⁴, Christian Gilissen ¹, Andreas R Janecke ¹⁵, Alexander Hoischen ¹⁶, Martin Zenker ²

Affiliations

1 Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
2 Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany.
3 Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.
4 Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
5 Center for Fetal Medicine, Department of Obstetrics and Gynecology, Karolinska University Hospital, 17176 Stockholm, Sweden.
6 Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 17176 Stockholm, Sweden.
7 Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
8 Institut für Humangenetik, Universitätsklinikum Essen, 45122 Essen, Germany.
9 Institut für Humangenetik, Universität zu Lübeck, 23562 Lübeck, Germany.
10 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey.
11 Pediatrics Genetics Division, Pediatrics Department, Marmara University Medical Faculty, 34668 Istanbul, Turkey.
12 Division of Human Genetics, Innsbruck Medical University, 6020 Innsbruck, Austria.
13 Department of Pediatrics, University of California, San Francisco, Fresno, CA 93701, USA.
14 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H8L1, Canada.
15 Division of Human Genetics, Innsbruck Medical University, 6020 Innsbruck, Austria; Department of Pediatrics I, Innsbruck Medical University, 6020 Innsbruck, Austria. Electronic address: [email protected].
16 Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: [email protected].

PMID: 25152457 DOI: 10.1016/j.ajhg.2014.07.012

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.

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