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Hum Genome Var. 2016 Dec 8;3:16042. doi: 10.1038/hgv.2016.42. eCollection 2016.

Digenic mutations of human OCRL paralogs in Dent's disease type 2 associated with Chiari I malformation.

Author information

1
Department of Neurosurgery, Yale School of Medicine , New Haven, CT, USA.
2
Department of Genetics, Yale School of Medicine , New Haven, CT, USA.
3
Department of Genetics, Yale School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
4
Division of Nephrology and Hypertension, Mayo Clinic College of Medicine , Rochester, MN, USA.
5
Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
6
Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA; O'Brien Urology Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
7
Yale Center for Genome Analysis, Yale School of Medicine, Yale University , New Haven, CT, USA.
8
Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
9
Howard Hughes Medical Institute , Chevy Chase, MD, USA.
10
Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.

Abstract

OCRL1 and its paralog INPP5B encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in OCRL1 cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in INPP5B have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression. Sequencing revealed a novel, de novo DD2-causing 462 bp deletion disrupting exon 3 of OCRL1 and a maternally inherited, extremely rare (ExAC allele frequency 8.4×10-6) damaging missense mutation in INPP5B (p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein's critical PH domain. In silico analyses of mutation impact predicted by SIFT, PolyPhen2, MetaSVM and CADD algorithms were all highly deleterious. Together, our findings report a novel association of DD2 with Chiari I malformation and syringohydromyelia, and document the effects of digenic mutation of human OCRL paralogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP3 metabolism in this mechanism.

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