Two novel mutations identified in familial cases with Donohue syndrome.
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.
Institute of Human Genetics, Western Galilee Medical Center Naharia, Israel ; Faculty of Medicine in Galilee, Bar-Ilan University Safed, Israel.
Tzipora C
TC
Falik Zaccai
Institute of Human Genetics, Western Galilee Medical Center Naharia, Israel.
Limor
L
Kalfon
Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School Jerusalem, Israel.
Aharon
A
Klar
Department of Neonatology, Western Galilee Medical Center Naharia, Israel.
Mordechai Ben
MB
Elisha
Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School Jerusalem, Israel.
Haggit
H
Hurvitz
Department of Pathology, Sackler School of Medicine, Tel Aviv University Tel Aviv, Israel.
Galina
G
Weingarten
Sherutei Briut Clalit Western Galilee District, Israel.
Emelia
E
Chechik
Department of Neonatology, Western Galilee Medical Center Naharia, Israel.
Vered
V
Fleisher Sheffer
Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School Jerusalem, Israel.
Raid
R
Haj Yahya
Department of Pathology, Sackler School of Medicine, Tel Aviv University Tel Aviv, Israel.
Gal
G
Meidan
Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School Jerusalem, Israel.
Eva
E
Gross-Kieselstein
Department of Obstetrics and Gynecology, Bikur Cholim General Hospital Jerusalem, Israel.
Dvora
D
Bauman
Department of Neonatology, Western Galilee Medical Center Naharia, Israel.
Sylvia
S
Hershkovitz
Genetics Institute, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University Tel Aviv, Israel.
Yuval
Y
Yaron
Genetics Institute, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University Tel Aviv, Israel.
Avi
A
Orr-Urtreger
Department of Pathology, Sackler School of Medicine, Tel Aviv University Tel Aviv, Israel.
Efrat
E
Wertheimer
Cardiomyopathy; Donohue syndrome; genotype–phenotype; insulin receptor.