Mutations in the insulin receptor (INSR) gene are responsible for Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). Insulin resistance is a feature of both diseases. Our patient was a Chinese neonate suffering from abnormal glucose homeostasis, hyperinsulinemia, dry skin, heavy hair, growth retardation and an elevated testosterone level. To search for candidate point mutations, small insertions or deletions and copy number variants, 2742 inherited disease-gene panel sequencing was performed. One pathogenic mutation (c.3355C>T, p.Arg1119Trp) and a novel 2.43Kb deletion (chr19:7150507-7152938) in INSR were found. The patient was diagnosed as RMS. Sanger sequencing and real-time quantitative polymerase chain reaction (PCR) confirmed the missense variant and microdeletion, respectively. We therefore supposed that these variants were candidate mutations in this case. We report a novel 2.43Kb deletion in INSR gene and provide further proof of the power of next generation sequencing in rare disease diagnosis.
Nijim Y, Awni Y, Adawi A, Bowirrat A. Classic Case Report of Donohue Syndrome (Leprechaunism; OMIM *246200): The Impact of Consanguineous Mating. Medicine (Baltimore) 2016;95:e2710.
Grasso V, Colombo C, Favalli V, Galderisi A, Rabbone I, Gombos S, Bonora E, Massa O, Meschi F, Cerutti F, Iafusco D, Bonfanti R, Monciotti C, Barbetti F. Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR? Acta Diabetol 2013;50:951-957. Epub 2013 Jul 4
Desbois-Mouthon C, Girodon E, Ghanem N, Caron M, Pennerath A, Conteville P, Magre J, Besmond C, Goossens M, Capeau J, Amselem S. Molecular analysis of the insulin receptor gene for prenatal diagnosis of leprechaunism in two families. Prenat Diagn 1997;17:657-663.
Backenroth D, Homsy J, Murillo LR, Glessner J, Lin E, Brueckner M, Lifton R, Goldmuntz E, Chung WK, Shen Y. CANOES: detecting rare copy number variants from whole exome sequencing data. Nucleic Acids Res 2014;42:e97. Epub 2014 Apr 25
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. The Protein Data Bank. Nucleic Acids Res 2000;28:235-242.
Brown RJ, Cochran E, Gorden P. Metreleptin improves blood glucose in patients with insulin receptor mutations. J Clin Endocrinol Metab 2013;98:1749-1756. Epub 2013 Aug 22
Simpkin A, Cochran E, Cameron F, Dattani M, de Bock M, Dunger DB, Forsander G, Guran T, Harris J, Isaac I, Hussain K, Kleta R, Peters C, Tasic V, Williams R, Yap Kok Peng F, O’’Rahilly S, Gorden P, Semple RK, Bockenhauer D. Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations. Nephron Physiol 2014;128:55- 56. Epub 2014 Oct 24
Ardon O, Procter M, Tvrdik T, Longo N, Mao R. Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene. Mol Genet Metab Rep 2014;1:71-84.
Wertheimer E, Lu SP, Backeljauw PF, Davenport ML, Taylor SI. Homozygous deletion of the human insulin receptor gene results in leprechaunism. Nat Genet 1993;5:71-73.
Falik Zaccai TC, Kalfon L, Klar A, Elisha MB, Hurvitz H, Weingarten G, Chechik E, Fleisher Sheffer V, Haj Yahya R, Meidan G, Gross-Kieselstein E, Bauman D, Hershkovitz S, Yaron Y, Orr-Urtreger A, Wertheimer E. Two novel mutations identified in familial cases with Donohue syndrome. Mol Genet Genomic Med 2014;2:64-72. Epub 2013 Nov 14
Hubbard SR. The insulin receptor: both a prototypical and atypical receptor tyrosine kinase. Cold Spring Harb Perspect Biol 2013;5:a008946.
Siala-Sahnoun O, Dhieb D, Ben Thabet A, Hmida N, Belguith N, Fakhfakh F. First molecular diagnosis of Donohue syndrome in Africa: novel unusual insertion/deletion mutation in the INSR gene. Mol Biol Rep 2016;43:165-173. Epub 2016 Feb 13
Hubbard SR. Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J 1997;16:5572-5581.
Leavens KF, Birnbaum MJ. Insulin signaling to hepatic lipid metabolism in health and disease. Crit Rev Biochem Mol Biol 2011;46:200-215. Epub 2011 Apr 5
Longo N, Singh R, Griffin LD, Langley SD, Parks JS, Elsas LJ. Impaired growth in Rabson-Mendenhall syndrome: lack of effect of growth hormone and insulin-like growth factor-I. J Clin Endocrinol Metab 1994;79:799-805.
Wei C, Burren CP. Diagnostic and management challenges from childhood, puberty through to transition in severe insulin resistance due to insulin receptor mutations. Pediatr Diabetes 2017;18:835-838. Epub 2017 Jan 17
Nobile S, Semple RK, Carnielli VP. A novel mutation of the insulin receptor gene in a preterm infant with Donohue syndrome and heart failure. J Pediatr Endocrinol Metab 2012;25:363-366.
Marchand A, Atassi F, Mougenot N, Clergue M, Codoni V, Berthuin J, Proust C, Trégouët DA, Hulot JS, Lompré AM. miR-322 regulates insulin signaling pathway and protects against metabolic syndrome-induced cardiac dysfunction in mice. Biochim Biophys Acta 2016;1862:611-621. Epub 2016 Jan 13
Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, Gorden P. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore) 2004;83:209-222.
de Kerdanet M, Caron-Debarle M, Nivot S, Gaillot T, Lascols O, Fremont B, Bonnaure-Mallet M, Gie S, Massart C, Capeau J. Ten-year improvement of insulin resistance and growth with recombinant human insulin-like growth factor 1 in a patient with insulin receptor mutations resulting in leprechaunism. Diabetes Metab 2015;41:331- 337. Epub 2014 Nov 25
Weber DR, Stanescu DE, Semple R, Holland C, Magge SN. Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome. J Pediatr Endocrinol Metab 2014;27:1237-1241.