A Homozygous Mutation in a Novel Zinc-Finger Protein, ERIS, Is Responsible for Wolfram Syndrome 2

A single missense mutation was identified in a novel, highly conserved zinc-finger gene, ZCD2, in three consanguineous families of Jordanian descent with Wolfram syndrome (WFS). It had been shown that these families did not have mutations in the WFS1 gene ( WFS1) but were mapped to the WFS2 locus at...

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Bibliographic Details
Published in:	American journal of human genetics Vol. 81; no. 4; pp. 673 - 683
Main Authors:	Amr, Sami, Heisey, Cindy, Zhang, Min, Xia, Xia-Juan, Shows, Kathryn H., Ajlouni, Kamel, Pandya, Arti, Satin, Leslie S., El-Shanti, Hatem, Shiang, Rita
Format:	Journal Article
Language:	English
Published:	Chicago, IL Elsevier Inc 01-10-2007 University of Chicago Press Cell Press American Society of Human Genetics
Subjects:	Amino Acid Sequence Amino Acid Substitution Amino acids Base Sequence Biological and medical sciences Calcium Calcium - metabolism Cells Cohort Studies Complex syndromes Consanguinity DNA - genetics Endoplasmic Reticulum - metabolism Female Fundamental and applied biological sciences. Psychology General aspects. Genetic counseling Genes Genetics of eukaryotes. Biological and molecular evolution Hearing loss Hearing Loss - genetics Homozygote Humans Male Medical genetics Medical sciences Membrane Proteins - genetics Membrane Proteins - metabolism Molecular and cellular biology Molecular Sequence Data Mutation Mutation, Missense Pedigree Proteins RNA Splicing Sequence Homology, Amino Acid Wolfram Syndrome - classification Wolfram Syndrome - genetics Wolfram Syndrome - metabolism Zinc Fingers - genetics Human Wolfram syndrome Structural unit Genetics Mutation Complex syndrome Homozygosity Protein Genetic disease
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Summary:	A single missense mutation was identified in a novel, highly conserved zinc-finger gene, ZCD2, in three consanguineous families of Jordanian descent with Wolfram syndrome (WFS). It had been shown that these families did not have mutations in the WFS1 gene ( WFS1) but were mapped to the WFS2 locus at 4q22-25. A G→C transversion at nucleotide 109 predicts an amino acid change from glutamic acid to glutamine (E37Q). Although the amino acid is conserved and the mutation is nonsynonymous, the pathogenesis for the disorder is because the mutation also causes aberrant splicing. The mutation was found to disrupt messenger RNA splicing by eliminating exon 2, and it results in the introduction of a premature stop codon. Mutations in WFS1 have also been found to cause low-frequency nonsyndromic hearing loss, progressive hearing loss, and isolated optic atrophy associated with hearing loss. Screening of 377 probands with hearing loss did not identify mutations in the WFS2 gene. The WFS1-encoded protein, Wolframin, is known to localize to the endoplasmic reticulum and plays a role in calcium homeostasis. The ZCD2-encoded protein, ERIS ( endoplasmic reticulum intermembrane small protein), is also shown to localize to the endoplasmic reticulum but does not interact directly with Wolframin. Lymphoblastoid cells from affected individuals show a significantly greater rise in intracellular calcium when stimulated with thapsigargin, compared with controls, although no difference was observed in resting concentrations of intracellular calcium.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0002-9297 1537-6605
DOI:	10.1086/520961