title: First molecular diagnosis of Donohue syndrome in Africa: novel unusual insertion/deletion mutation in the INSR gene.
abstract: Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million life births. It represents the most severe form of insulin resistance due to mutations involving the insulin receptor (IR) gene "INSR". DS is characterized by pre- and postnatal growth retardation with failure-to-thrive, lipoatrophy, acanthosis nigricans, hypertrichosis, and dysmorphic features. An exhaustive INSR gene sequencing was performed after PCR amplification of coding exons and introns boundaries. Bioinformatic tools, including ESEfinder, MFOLD and Proter software were also used to predict the impact of INSR mutation on INSR on gene expression as well as on the protein structure and function. The results have shown a novel unusual c.3003_3012delinsGGAAG (p.S1001_D1004delinsRE) insertion/deletion (indel) mutation within the exon 16 in the three patients, which represent the fourth indel mutation within the INSR gene. The mutation modifies the secondary structure of DNA and RNA, as well as the composition of exonic splicing enhancers of exon 16. Moreover, despite the conservation of the secondary structure of the IR, the p.S1001_D1004delinsRE in-frame mutation is accompanied by the loss of four amino acids replaced by two residues of different nature and hydrophobicity level in the juxtamembrane domain of the receptor. The results have confirmed the role of the juxtamembrane domain of IR involved in a crucial interaction of the IR with cellular effectors essentially the IR substrate 1 (IRS-1), the SHC and the Nck proteins that ensure the signal mediated by the insulin transduction pathway in target cells. Our findings have also proven the genotype/phenotype correlation between INSR mutation and DS phenotype severity.
authors.affiliation: Live Sciences Department, Faculty of Sciences of Sfax, Sfax, Tunisia. olfasiala9@gmail.com.
authors.forename: Olfa
authors.initials: O
authors.lastname: Siala-Sahnoun
authors.affiliation: Laboratory of Human Molecular Genetics, Medicine Faculty of Sfax, Sfax, Tunisia.
authors.forename: Dhoha
authors.initials: D
authors.lastname: Dhieb
authors.affiliation: Neonatology Service, EPS Hédi Chaker, Sfax, Tunisia.
authors.forename: Afef
authors.initials: A
authors.lastname: Ben Thabet
authors.affiliation: Neonatology Service, EPS Hédi Chaker, Sfax, Tunisia.
authors.forename: Nedia
authors.initials: N
authors.lastname: Hmida
authors.affiliation: Laboratory of Medical Genetics, EPS Hédi Chaker, Sfax, Tunisia.
authors.forename: Neila
authors.initials: N
authors.lastname: Belguith
authors.affiliation: Live Sciences Department, Faculty of Sciences of Sfax, Sfax, Tunisia.
authors.forename: Faiza
authors.initials: F
authors.lastname: Fakhfakh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000349:Africa; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D056731:Donohue Syndrome / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D054643:INDEL Mutation; D007223:Infant; D007231:Infant, Newborn; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism; D017433:Protein Structure, Secondary; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C078332:Nck protein; D015513:Oncogene Proteins; D055765:Shc Signaling Adaptor Proteins; C435941:INSR protein, human; D011972:Receptor, Insulin
keywords: Donohue syndrome; Exonic splicing enhancer; INSR gene; Indel mutation; Insulin receptor