title: Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype.
abstract: Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic β-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants.
authors.affiliation: Tuscany Regional Centre of Pediatric Diabetes, Meyer University Children's Hospital, Florence, Italy. Electronic address: b.piccini@meyer.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Piccini
authors.affiliation: Medical Genetics Unit, Meyer University Children's Hospital, Florence, Italy.
authors.forename: Rosangela
authors.initials: R
authors.lastname: Artuso
authors.affiliation: Tuscany Regional Centre of Pediatric Diabetes, Meyer University Children's Hospital, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Lenzi
authors.affiliation: Tuscany Regional Centre of Pediatric Diabetes, Meyer University Children's Hospital, Florence, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Guasti
authors.affiliation: Tuscany Regional Centre of Pediatric Diabetes, Meyer University Children's Hospital, Florence, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Braccesi
authors.affiliation: Tuscany Regional Centre of Pediatric Diabetes, Meyer University Children's Hospital, Florence, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Barni
authors.affiliation: University of Florence, Florence, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Casalini
authors.affiliation: Medical Genetics Unit, Meyer University Children's Hospital, Florence, Italy; Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
authors.affiliation: Tuscany Regional Centre of Pediatric Diabetes, Meyer University Children's Hospital, Florence, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Toni
mesh_terms: D000293:Adolescent; D000818:Animals; D002219:Carbamates / Q000008:administration & dosage; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010880:Piperidines / Q000008:administration & dosage; D000071701:Regulatory Factor X Transcription Factors / Q000235:genetics
chemical_list: D002219:Carbamates; D007328:Insulin; D010880:Piperidines; D000071701:Regulatory Factor X Transcription Factors; C547964:Rfx6 protein, human; C072379:repaglinide
keywords: Children; MODY; Monogenic diabetes; Next generation sequencing; β-Cell