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We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype\u2013phenotype issues playing a role in the pathophysiology of DS. A female infant born to first\u2010degree cousins Muslim Arab parents and two brothers born to first\u2010degree 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 <jats:italic>INSR<\/jats:italic> 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 <jats:italic>INSR<\/jats:italic> which appear to impair post\u2010translational 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.<\/jats:p>","DOI":"10.1002\/mgg3.43","type":"journal-article","created":{"date-parts":[[2013,11,14]],"date-time":"2013-11-14T10:27:50Z","timestamp":1384424870000},"page":"64-72","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Two novel mutations identified in familial cases with Donohue syndrome"],"prefix":"10.1002","volume":"2","author":[{"given":"Tzipora C.","family":"Falik Zaccai","sequence":"first","affiliation":[{"name":"Institute of Human Genetics Western Galilee Medical Center Naharia Israel"},{"name":"Faculty of Medicine in Galilee Bar\u2010Ilan University Safed Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limor","family":"Kalfon","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Western Galilee Medical Center Naharia 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