title: Digenic mutations of humanOCRLparalogs in Dent's disease type 2 associated with Chiari I malformation.
abstract: OCRL1and its paralogINPP5Bencode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations inOCRL1cause 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 inINPP5Bhave 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 novoDD2-causing 462 bp deletion disrupting exon 3 ofOCRL1and a maternally inherited, extremely rare (ExAC allele frequency 8.4×10-6) damaging missense mutation inINPP5B(p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein's critical PH domain.In silicoanalyses 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 humanOCRLparalogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP3metabolism in this mechanism.
authors.affiliation: Department of Neurosurgery, Yale School of Medicine , New Haven, CT, USA.
authors.forename: Daniel
authors.identifier: 0000-0001-6888-252X
authors.initials: D
authors.lastname: Duran
authors.affiliation: Department of Genetics, Yale School of Medicine , New Haven, CT, USA.
authors.forename: Sheng Chih
authors.initials: SC
authors.lastname: Jin
authors.affiliation: Department of Neurosurgery, Yale School of Medicine , New Haven, CT, USA.
authors.forename: Tyrone
authors.initials: T
authors.lastname: DeSpenza
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic College of Medicine , Rochester, MN, USA.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cogal
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic College of Medicine , Rochester, MN, USA.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Abrash
authors.affiliation: 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.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.affiliation: 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.
authors.forename: John C
authors.initials: JC
authors.lastname: Lieske
authors.affiliation: Department of Neurosurgery, Yale School of Medicine , New Haven, CT, USA.
authors.forename: Serena Je
authors.initials: SJ
authors.lastname: Shimshak
authors.affiliation: Yale Center for Genome Analysis, Yale School of Medicine, Yale University , New Haven, CT, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: Yale Center for Genome Analysis, Yale School of Medicine, Yale University , New Haven, CT, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Department of Neurosurgery, Yale School of Medicine , New Haven, CT, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: DiLuna
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
authors.affiliation: Howard Hughes Medical Institute , Chevy Chase, MD, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: 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.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle