Two novel mutations identified in familial cases with donohue syndrome

Tzipora C. Falik Zaccai, Limor Kalfon, Aharon Klar, Mordechai Ben Elisha, Haggit Hurvitz, Galina Weingarten, Emelia Chechik, Vered Fleisher Sheffer, Raid Haj Yahya, Gal Meidan, Eva Gross-Kieselstein, Dvora Bauman, Sylvia Hershkovitz, Yuval Yaron, Avi Orr-Urtreger, Efrat Wertheimer

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype–phenotype issues playing a role in the pathophysiology of DS. A female infant born to first-degree cousins Muslim Arab parents and two brothers born to first-degree cousins Druze parents presented classical features of DS with hypertrophic cardiomyopathy and died in infancy. Each patient was found homozygous for one missense mutation within the extracellular domain of the INSR gene. Western blot analysis identified the proreceptor of INSR, but not its mature subunits alpha and beta. Of 95 healthy Muslims, no heterozygous was found and of 52 healthy Druze from the same village, one was heterozygous. This study presents two novel familial mutations in the alpha subunit of the INSR which appear to impair post-translational processing of the INSR, resulting loss of its function. Both mutations cause DS with hypertrophic cardiomyopathy and early death. Identification of the causative mutation enables prevention of this devastating disease.

Original languageEnglish
Pages (from-to)64-72
Number of pages9
JournalMolecular genetics & genomic medicine
Volume2
Issue number1
DOIs
StatePublished - Jan 2014

Bibliographical note

Publisher Copyright:
© 2013 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Keywords

  • Cardiomyopathy
  • Donohue syndrome
  • Genotype–phenotype
  • Insulin receptor

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