Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young

Dušátková, Lenka; Dušátková, Petra; Vosáhlo, Jan; Vesela, Klara; Cinek, Ondřej; Lebl, Jan; Průhová, Štěpánka

doi:10.1016/j.ejmg.2015.02.004

Cited by 21 publications

(16 citation statements)

References 24 publications

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“…In an initial report, patients with the c.188‐31G>A mutation were diagnosed at 1 month after birth. However, the ages at diagnosis observed in another two families reported were older than that of the initial report and were similar to the present patients (Table ), suggesting that other genetic and environmental factors might modulate the age at onset of diabetes.…”

Section: Discussionsupporting

confidence: 84%

Identification of a variant associated with early‐onset diabetes in the intron of the insulin gene with exome sequencing

Matsuno

Furuta

Kosaka

et al. 2018

J of Diabetes Invest

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Whole‐exome sequencing is a new technology. We used it to explore the gene responsible for early‐onset diabetes as a result of impaired insulin secretion in a family. In the INS gene, we identified the heterozygous c.188‐31G>A mutation in the proband – a 43‐year‐old woman. The mutation was also identified in her two daughters with diabetes, but not in her son or her parents, all of whom did not have diabetes. The substitution was located 31 bp proximal to exon 3 in intron 2. It was predicted to create an ectopic splice site leading to inserting 29 nucleotides of intron 2 as an exonic sequence in the transcript. The mutation has been reported in White families, and the present case is the first report in an Asian person. The present results would help in understanding the role of the mutation in developing diabetes.

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Section: Discussionsupporting

confidence: 84%

Identification of a variant associated with early‐onset diabetes in the intron of the insulin gene with exome sequencing

Matsuno

Furuta

Kosaka

et al. 2018

J of Diabetes Invest

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“…In addition to the normoglycemic maternal grandfather (at the time of writing aged 83 years, BMI 22.2 kg/m 2 , FCP 1956.8 pmol/L) and younger brother (at the time of writing aged 9 years, BMI 16.7 kg/m 2 , FCP 1020.2 pmol/L), the remaining five members of the family had had various diabetes phenotypes since the ages of 15, 36, 45, 34 and 24 years. A wide spectrum of clinical manifestations has been reported in INS gene mutations even within a single family, especially considerable differences in residual β‐cell function . Clinical heterogeneity in terms of the age at diagnosis, manifestations and therapeutic options are also evident in the present case.…”

Section: Discussionmentioning

confidence: 64%

Novel frameshift mutation in the insulin (INS) gene in a family with maturity onset diabetes of the young (MODY)

Xiao

Liu

Xiao

et al. 2018

Journal of Diabetes

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“…It is rare that prolongation of protein causing by frameshift mutation, and it was not reported in PAX6 by previous studies. We retrieved one case that a deletion mutation of insulin ( INS ) gene predicted to prolong amino acid sequence which rarely occurred in patients with maturity onset diabetes of the young (MODY) (Dusatkova et al., ). The mutation c.1192delT (p.S398Pfs*126), in our study, loses the original stop codon resulting in a prolonged protein molecule in this study, which contains an additional 102 amino acids.…”

Section: Discussionmentioning

confidence: 99%

Extension of the mutation spectrum of PAX6 from three Chinese congenital aniridia families and identification of male gonadal mosaicism

Bai

Kong

2018

Molec Gen & Gen Med

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BackgroundCongenital aniridia is a severe autosomal dominant binocular developmental disorder, the primary feature of which is congenital absence or hypoplasia of the iris. PAX6 is the main disease‐causing gene of congenital aniridia; inheritance is autosomal dominant. But the current mutations do not fully explain this disorder.MethodsWe investigated the mutation profile of genes related in three Chinese families with congenital aniridia through targeted sequencing technology. And we validated the candidate variants by PCR‐based Sanger sequencing. Different degree impairments of islet function were observed in the patients with aniridia by carbohydrate tolerance butter and insulin release tests in our study.ResultsWe identified four novel mutations of PAX6 from three Chinese families with congenital aniridia, which included heterozygous double mutation c.879_880delCA (p.S294Cfs*46) and c.1124C>G (p.P375R) in Family 1 with three patients, heterozygous frameshift mutation c.308delG (p.P103Qfs*21) in Family 2 with one patient, and c.1192delT (p.S398Pfs*126) in Family 3 with two patients. The three frameshift mutations of PAX6 are co‐segregated with the aniridia from controls in the families, but the novel missense mutation is not co‐segregated with the phenotype. The frameshift mutations in Family 1 and Family 2 have effects to truncate the protein, but the frameshift mutation in Family 3 will prolong it. We confirmed the phenomenon of male gonadal mosaicism of PAX6 by the sequencing of two linked novel mutations in Family 1. Most of the patients with isolated aniridia have different degrees of islet damage through related clinical tests.ConclusionIt is therefore noteworthy that we found different types of pathogenic mutation, which have effects of truncating or prolonging protein leaded by frameshift mutation. Our results of this study extended the pathogenic mutation spectrum of PAX6 for congenital aniridia and demonstrated the male germline chimerism by molecular experiments.

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Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young

Cited by 21 publications

References 24 publications

Identification of a variant associated with early‐onset diabetes in the intron of the insulin gene with exome sequencing

Identification of a variant associated with early‐onset diabetes in the intron of the insulin gene with exome sequencing

Novel frameshift mutation in the insulin (INS) gene in a family with maturity onset diabetes of the young (MODY)

Extension of the mutation spectrum of PAX6 from three Chinese congenital aniridia families and identification of male gonadal mosaicism

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