Review on monogenic diabetes
ABSTRACT The goal of this review is to provide an update on the different forms of monogenic diabetes, including maturity-onset diabetes of the young (MODY) and neonatal diabetes (permanent and transient neonatal diabetes).
Monogenic diabetes accounts for approximately 1-2% of diabetes cases and results from mutations that primarily reduce β-cell function. Individuals with islet autoantibody negative youth-onset forms of diabetes should be evaluated for either glucokinase-MODY or transcription factors MODY. The mild-fasting hyperglycemia found in glucokinase-MODY typically does not necessitate pharmacological treatment, whereas patients with MODY caused by transcription factor mutations can often be successfully treated with low-dose sulfonylurea. Neonatal diabetes is defined as diabetes onset within the first 6 months of life and most individuals with permanent neonatal diabetes can be treated with high-dose sulfonylurea.
The discovery of the genetic cause of monogenic diabetes has greatly advanced our understanding and management of these uncommon forms of diabetes.
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ABSTRACT: Diabetes mellitus and neurodegeneration are common diseases for which shared genetic factors are still only partly known. Here, we show that loss of the BiP (immunoglobulin heavy-chain binding protein) co-chaperone DNAJC3 leads to diabetes mellitus and wide-spread neurodegeneration. We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy. Exome sequencing identified a homozygous stop mutation in DNAJC3. Screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion. DNAJC3 was absent in fibroblasts from all affected subjects in both families. To delineate the phenotypic and mutational spectrum and the genetic variability of DNAJC3, we analyzed 8,603 exomes, including 506 from families affected by diabetes, ataxia, upper-motor-neuron damage, peripheral neuropathy, or hearing loss. This anal-ysis revealed only one further loss-of-function allele in DNAJC3 and no further associations in subjects with only a subset of the features of the main phenotype. Our findings demonstrate that loss-of-function DNAJC3 mutations lead to a monogenic, recessive form of diabetes mellitus in humans. Moreover, they present a common denominator for diabetes and widespread neurodegeneration. This complements findings from mice in which knockout of Dnajc3 leads to diabetes and modifies disease in a neurodegenerative model of Marinesco-Sjögren syndrome. Nonautoimmune diabetes mellitus and neurodegenera-tion are common disorders for which shared genetic factors are still only partly known. Monogenic forms of diabetes include neonatal diabetes (MIM 606176) and maturity-onset diabetes of the young (MIM 606391), both of which arise from mutations that primarily reduce pancreatic b cell function. 1 Although monogenicThe American Journal of Human Genetics 11/2014; 95(6). DOI:10.1016/j.ajhg.2014.10.013 · 10.99 Impact Factor
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ABSTRACT: Genetic sequencing has become a critical part of the diagnosis of certain forms of pancreatic beta cell dysfunction. Despite great advances in the speed and cost of DNA sequencing, determining the pathogenicity of variants remains a challenge, and requires sharing of sequence and phenotypic data between laboratories. We reviewed all diabetes and hyperinsulinism-associated molecular testing done at the Seattle Children’s Molecular Genetics Laboratory from 2009-2013. 331 probands were referred to us for molecular genetic sequencing for Neonatal Diabetes (NDM), Maturity-Onset Diabetes of the Young (MODY), or Congenital Hyperinsulinism (CHI) during this period. Reportable variants were identified in 115 (35%) patients with 91 variants in one of 6 genes: HNF1A, GCK, HNF4A, ABCC8, KCNJ11, or INS. In addition to identifying 23 novel variants, we identified unusual mechanisms of inheritance, including mosaic and digenic MODY presentations. Re-analysis of all reported variants using more recently available databases led to a change in variant interpretation from the original report in 30% of cases. These results represent a resource for molecular testing of monogenic forms of diabetes and hyperinsulinism, providing a mutation spectrum for these disorders in a large North American cohort. In addition, they highlight the importance of periodic review of molecular testing results.Molecular Genetics and Metabolism 12/2014; 114(3). DOI:10.1016/j.ymgme.2014.12.304 · 2.83 Impact Factor
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ABSTRACT: The murine Mafa transcription factor is a key regulator of postnatal islet β-cell activity, affecting insulin transcription, insulin secretion, and β-cell mass. Human MAFA expression is also markedly decreased in islet β-cells of Type 2 diabetes mellitus (T2DM) patients. Moreover, levels are profoundly reduced in db/db islet β-cells, a mouse model of T2DM. To examine the significance of this key islet β-cell-enriched protein to glycemic control under diabetic conditions, we generated transgenic mice that conditionally and specifically produced Mafa in db/db islet β-cells. Sustained expression of Mafa resulted in significantly lower plasma glucose levels, higher plasma insulin and augmented islet β-cell mass. In addition, there was increased expression of insulin, Slc2a2, and newly identified Mafa regulated genes involved in reducing β-cell stress, like Gsta1 and Gckr. Importantly, the levels of human GSTA1 were also compromised in T2DM islets. Collectively, these results illustrate how consequential the reduction in Mafa activity is to islet β-cell function under pathophysiological conditions. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.Journal of Biological Chemistry 02/2015; 290(12). DOI:10.1074/jbc.M114.595579 · 4.60 Impact Factor