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Am J Hum Genet. 2019 Aug 1;105(2):384-394. doi: 10.1016/j.ajhg.2019.05.019. Epub 2019 Jun 27.

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Author information

1
Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
2
Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
3
Insitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, 53127 Bonn, Germany.
4
Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
5
Clinical Genetics Department, Nottingham University Hospitals NHS Trust, Nottingham NGS 1PB, UK.
6
Centre Hospitalier Universitaire de Québec, 2705 Boulevard Laurier, Ville de Québec, QC G1V 4G2, Canada.
7
Department of Pediatrics, School of Medicine, Iwate Medical University, Morioka, Iwate 020-8505, Japan.
8
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
9
Centrum Medische Genetica Antwerpen, 2650 EDEGEM, Belgium.
10
Institute of Human Genetics, University Hospital of Cologne, and Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany.
11
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
12
Deparment of Biology and Microbiology, Riga Stradinš University, Riga, LV-1029, Latvia.
13
Children's Clinical University Hospital, Riga, LV-1004, Latvia.
14
Latvian Biomedical Research and Study Centre, Ratsupites Str. 1 k-1, Riga LV-1067, Latvia.
15
Department of Medical Genetics, Children's Hospital of Pittsburgh of University Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
16
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi 110060, India.
17
Department of Inborn Errors of Metabolism, Dr. von Hauner Children's Hospital, 80337 Munich, Germany.
18
Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72074 Tübingen, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
19
Department of Paediatric Neurology, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
20
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
21
Dept of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
22
CENTOGENE AG, The Rare Disease Company, 18055 Rostock, Germany.
23
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
24
Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Neurosciences, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC H3T 1C5, Canada.
25
Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan. Electronic address: tkinoshi@biken.osaka-u.ac.jp.
26
Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address: p.campeau@umontreal.ca.

Abstract

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.

KEYWORDS:

DOORS syndrome; PIGB; alkaline phosphatase; epilepsy; glycosylphosphatidylinositol; inherited GPI deficiency (IGD); intellectual disability; neuropathy; seizures

PMID:
31256876
DOI:
10.1016/j.ajhg.2019.05.019

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