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FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.


ABSTRACT: Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.

SUBMITTER: Hwang JL 

PROVIDER: S-EPMC5918222 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

Hwang Jessica L JL   Park Soo-Young SY   Ye Honggang H   Sanyoura May M   Pastore Ashley N AN   Carmody David D   Del Gaudio Daniela D   Wilson Janna F JF   Hanis Craig L CL   Liu Xiaoming X   Atzmon Gil G   Glaser Benjamin B   Philipson Louis H LH   Greeley Siri Atma W SAW  

Pediatric diabetes 20171129 3


Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and  ...[more]

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