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Two Novel Mutations Identified in Familial Cases with Donohue

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Two Novel Mutations Identified in Familial Cases with Donohue ORIGINAL ARTICLE Two novel mutations identified in familial cases with Donohue syndrome Tzipora C. Falik Zaccai1,2, Limor Kalfon1, Aharon Klar3, Mordechai Ben Elisha4, Haggit Hurvitz3, Galina Weingarten5, Emelia Chechik6, Vered Fleisher Sheffer4, Raid Haj Yahya3, Gal Meidan5, Eva Gross-Kieselstein3, Dvora Bauman7, Sylvia Hershkovitz4, Yuval Yaron8, Avi Orr-Urtreger8 & Efrat Wertheimer5 1Institute of Human Genetics, Western Galilee Medical Center, Naharia, Israel 2Faculty of Medicine in Galilee, Bar-Ilan University, Safed, Israel 3Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School, Jerusalem, Israel 4Department of Neonatology, Western Galilee Medical Center, Naharia, Israel 5Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 6Sherutei Briut Clalit, Western Galilee District, Israel 7Department of Obstetrics and Gynecology, Bikur Cholim General Hospital, Jerusalem, Israel 8Genetics Institute, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Keywords Abstract Cardiomyopathy, Donohue syndrome, genotype–phenotype, insulin receptor. Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin Correspondence resistance, severe growth retardation, hypertrichosis, and characteristic dysmor- Tzipora C. Falik-Zaccai, Institute of Human phic features. We report the clinical, molecular, and biochemical characterization Genetics, Western Galilee Medical Center – of three new patients with DS, and address genotype–phenotype issues playing a Naharia, P.O. Box 21, Naharia 22100. Israel. role in the pathophysiology of DS. A female infant born to first-degree cousins Tel: 972-50-7887-941; Fax: 972-4-9107553; Muslim Arab parents and two brothers born to first-degree cousins Druze parents E-mail: [email protected] presented classical features of DS with hypertrophic cardiomyopathy and died in Funding Information infancy. Each patient was found homozygous for one missense mutation within The research was funded in part by the the extracellular domain of the INSR gene. Western blot analysis identified the Israeli Ministry of Justice, Keren Izvonot for proreceptor of INSR, but not its mature subunits alpha and beta. Of 95 healthy Mapping genes for rare diseases in the Muslims, no heterozygous was found and of 52 healthy Druze from the same vil- northern Galilee (to T.C. Falik-Zaccai). lage, one was heterozygous. This study presents two novel familial mutations in the alpha subunit of the INSR which appear to impair post-translational process- Received: 1 July 2013; Revised: 23 September 2013; Accepted: 24 September ing of the INSR, resulting loss of its function. Both mutations cause DS with 2013 hypertrophic cardiomyopathy and early death. Identification of the causative mutation enables prevention of this devastating disease. Molecular Genetics & Genomic Medicine 2014; 2(1): 64–72 doi: 10.1002/mgg3.43 Introduction Mendenhall syndrome, and type A insulin resistance are autosomal recessive (AR) disorders caused by biallelic Single-gene defects are responsible for hyperglycemia in mutations in the gene encoding the insulin receptor only a minority of individuals. Mutations affecting both (INSR, OMIM#147670). These syndromes, sharing pheno- insulin production and insulin sensitivity have been iden- type and genotype heterogeneity, are distinguished from tified. Maturity onset diabetes in the young is a mono- one another based on the severity of symptoms, age of genic type of diabetes in which a mutation in an onset, and age of death (Porter and Barrett 2005). DS is autosomal dominant gene disrupts insulin production considered the most severe syndrome of the group, and is (Winckler et al. 2007). Donohue syndrome (DS, usually lethal within 2 years of life (Musso et al. 2004; OMIM#246200), also known as Leprechaunism, Rabson– Semple et al. 2011; Grasso et al. 2013). 64 ª 2013 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. T. C. Falik Zaccai et al. The Insulin Receptor Gene and the Heart Donohue syndrome is characterized by markedly delayed were performed. Biochemical workup included renal and linear growth and failure to thrive (FTT), loss of glucose liver function tests, glucose, insulin, C-peptide, and gluca- homeostasis, hyperinsulinemia, thick skin with lack of subcu- gon levels. Blood was drawn for molecular studies, and taneous fat, acanthosis nigricans (AN), distended abdomen, fibroblast cells cultures were established from skin biopsies enlarged genitalia in the male and cystic ovaries in the female, of patients ISR1 and ISR2 as previously described (Falik- and dysmorphic facial features: elfin faces with prominent Zaccai et al. 2008b). eyes, thick lips, upturned nostrils, and low-set posterior rotated ears (Geffner et al. 1987; al-Gazali et al. 1993). A wide spectrum of disorders caused by diverse mono- Mutation analysis in the insulin receptor genic etiologies resembles DS. Specifically, Berardinelli– gene Seip congenital lipodystrophy is a condition associating For patient ISR 1 insulin resistance, absence of subcutaneous fat, AN, and muscular hypertrophy caused by mutation in either AG- Studies were carried to locate the INSR underlying muta- PAT2 (OMIM#603100) or BSCL2 (OMIM# 606158) (Fri- tion by denaturing high-performance liquid chromatogra- guls et al. 2009; Miranda et al. 2009), AN associating with phy (dHPLC) of each of the 22 INSR exons, including severe skeletal dysplasias due to activating mutations in exon-intron boundaries. Exons demonstrating abnormal FGFR3 (OMIM#134934) (Alatzoglou et al. 2009) are just a pattern, compared with control, in the dHPLC screening few examples. were further sequenced for determining possible DNA The association between diabetes and cardiovascular polymorphism. Results were confirmed using Allele-spe- disease is well recognized (Kannel and McGee 1979). cific oligonucleotide (ASO) using radiolabelled oligoprobes: ′ ′ ′ Furthermore, evidence for insulin resistance has been 5 -TCAGCTTCTGCCAGGACC-3 (wild type) and 5 -TC ′ shown to associate with cardiovascular disease, and spe- AGCTTCTACCAGGACC-3 (mutant). Population screen- cifically, with hypertrophic cardiomyopathy (HCM), also ing of 95 Arab Muslims was carried out using Sanger in individuals without diabetes (Murakami et al. 2004; sequencing of a 347 bp amplicon containing the p.C286Y Bonora et al. 2007; Verhagen et al. 2011). Recently, a mutation (Macrogen Inc, Amsterdam, Netherlands). large meta-analysis substantiated the association between metabolic syndrome and cardiovascular disease (Mottillo For patients 2 and 3 et al. 2010). Insulin resistance is a central component of both metabolic syndrome and DS. Several reports The 22 exons of the INSR (NM_000208.2) were Sanger (Baykan et al. 2008; Nobile et al. 2012; Hovnik et al. sequenced and analyzed using the ABI PRISM 3130 2013) argue that the underlying mechanisms for cardio- Genetic Analyzer (Applied Biosystems, Warrington, U.K.) myopathy in DS and metabolic syndrome involve excess according to the manufacturer’s instructions. insulin activation of Insulin-like growth factor 1 (IGF1) For the Druze patients, sequencing results were con- receptors [6]. firmed and healthy controls were examined by chain reac- In this study we characterized two novel missense tion (PCR) amplification of exon 2 using the primers: ′ ′ mutations in the INSR causing DS with HCM. INSR_ex2 (1) F: 5 - GAT GAA AAC ACA GGG CCC AG- 3 INSR_ex2(1) R: 5′- CTC CAC GGA ATC CAG GAT AC -3′ The reaction was followed by enzymatic digestion Material and Methods using the restriction enzyme TaqI (New England Biolabs, Ipswich, MA). Patients The patients were three newborns from two unrelated Immunoprecipitation and immunoblotting families who were hospitalized in neonatal intensive care analysis units: a female born to first-degree cousins Muslim Arab parents (named patient ISR1) and two brothers with first- Protein lysate was prepared according to standard proto- degree cousins Druze parents (named patients ISR2 and cols and studies were carried out as detailed elsewhere ISR3). The IRB of Nahariya Medical Center and the (Wertheimer et al. 1993). Antibodies used for immuno- Israeli Ministry of Health approved the study. blotting and immunoprecipitation procedures included monoclonal antibody recognizing phosphotyrosine resi- dues (Upstate Biotechnology, Inc., Lake Placid, NY) and Clinical examination rabbit polyclonal antibodies against the insulin receptor Family history was taken and physical examinations con- beta subunit (Santa Cruz Biotechnology, Inc., Santa Cruz, ducted. Imaging studies of the brain, abdomen, and heart CA). ª 2013 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. 65 The Insulin Receptor Gene and the Heart T. C. Falik Zaccai et al. the biochemical tests of the patients, are depicted in Prenatal diagnosis Figure 1 and summarized in Table 1, respectively. Prenatal diagnosis (PND) was performed for the Arab Muslim family. After comprehensive genetic counseling, Family 1 chorionic villous sampling (CVS) was performed. DNA was extracted from the villi and exon 3 of the INSR gene Patient ISR1, the second
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