CA8 Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait

Seval Türkmen,Masoud Garshasbi,Gao Guo,Claudia Mischung,Andreas Kuss,Katrin Hoffmann,Peter N Robinson,Stefan Mundlos,Nicholas Humphrey,Amjad J Alshalah,Gregory S Barsh

doi:10.1371/journal.pgen.1000487

Seval Türkmen, Masoud Garshasbi + Show 9 more

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https://doi.org/10.1371/journal.pgen.1000487

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Abstract

We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.

Highlights

The hereditary ataxias comprise a diverse groups of disorders characterized by loss of balance and coordination
A syndrome of nonprogressive cerebellar ataxia and mental retardation associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification was initially identified in patients with a disorder termed ‘‘dysequilibrium syndrome’’ (MIM 224050)
We identified a homozygous missense mutation (S100P) in the gene encoding carbonic anhydrase VIII in a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait

Summary

Introduction

The hereditary ataxias comprise a diverse groups of disorders characterized by loss of balance and coordination. A syndrome of nonprogressive cerebellar ataxia and mental retardation associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification was initially identified in patients with a disorder termed ‘‘dysequilibrium syndrome’’ (MIM 224050). This disorder was found to be due to a 199 kb deletion on chromosome 9p24 encompassing all of the very low-density lipoprotein receptor gene (VLDLR) and part of the poorly characterized gene LOC401491 [3]. An unrelated Iranian family with a PTC mutation in VLDLR was subsequently reported in which affected persons had mental retardation, strabismus, short stature, disturbed equilibrium, and walking disability, but no tendency towards quadrupedal gait [6]. A further unrelated family with cerebellar hypoplasia, mental retardation, and quadrupedal gait demonstrated linkage to a locus on chromosome 17p [7]

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