Two novel mutations identified in familial cases with Donohue syndrome

• Published in: Molecular genetics & genomic medicine Vol. 2; no. 1; pp. 64 - 72
• Main Authors: Falik Zaccai, Tzipora C., Kalfon, Limor, Klar, Aharon, Elisha, Mordechai Ben, Hurvitz, Haggit, Weingarten, Galina, Chechik, Emelia, Fleisher Sheffer, Vered, Haj Yahya, Raid, Meidan, Gal, Gross‐Kieselstein, Eva, Bauman, Dvora, Hershkovitz, Sylvia, Yaron, Yuval, Orr‐Urtreger, Avi, Wertheimer, Efrat
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-01-2014; Wiley Periodicals; Wiley
• Subjects: Abdomen; Age; Cardiomyopathy; Cardiovascular disease; Congenital diseases; Deoxyribonucleic acid; Diabetes; DNA; Donohue syndrome; Enzymes; Families & family life; Genetic counseling; Genotypes; genotype–phenotype; Growth factors; Growth rate; Hyperglycemia; Hypertrichosis; Hypoglycemia; Insulin; insulin receptor; Insulin resistance; Kidneys; Laboratories; Medical research; Metabolic syndrome; Missense mutation; Muslims; Mutation; Original; Ovaries; Parents & parenting; Patients; Peptides; Phenotypes; Pneumonia; Pregnancy; Studies; Ultrasonic imaging; genotype–phenotype; insulin receptor; Cardiomyopathy; Donohue syndrome
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.43

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.
In the present study we have conducted clinical evaluation of three patients presented classical features of leprechaunism. All three had cardiomyopathy and died in infancy. Genomic sequencing of INSR revealed that each patient was homozygous for one of two novel missense mutations within the extracellular domain of the INSR gene.