Positional Cloning of “Lisch-like”, a Candidate Modifier of Susceptibility to Type 2 Diabetes in Mice

In 404 Lepob/ob F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lepob. The phenotypes of B6.DBA congenic mice include reduced β-cell replication rates accompanied by reduced β-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated “Lisch-like” (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646–amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes

Mutation screening in 18 Caucasian families suggest the existence of other MODY genes

Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulin-dependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4 alpha/MODY1/TCF14) on chromosome 20 q, glucokinase (GCK/MODY2) on chromosome 7p, hepatocyte nuclear factor-1 alpha (HNF-1 alpha/MODY3/TCF1) on chromosome 12q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13q and hepatocyte nuclear factor-1 beta (HNF-1 beta/MODY5/TCF2) on chromosome 17cen-q. We have screened the HNF-4 alpha:, HNF-1 alpha and HNF-1 beta genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T --> A) and one deletion mutation (P379fsdelT) were found in the HNF-1 alpha gene, but no MODY-associated mutations were found in the HNF-4 alpha and HNF-1 beta genes. Of 67 French MODY families that we have now studied, 42 (63%) have mutations in the glucokinase gene, 14 (21%) have mutations in the HNF-1 alpha gene, and 11 (16%) have no mutations in the HNF-4 alpha, IPF1 and HNF-1 beta genes. Eleven families do not have mutations in the five known MODY genes suggesting that there is at least one additionnal locus that can cause MODY

Maturity-onset diabetes of the young (MODY): how many cases are we missing?

Maturity-onset diabetes of the young is frequently misdiagnosed as type 1 or type 2 diabetes. A correct diagnosis of MODY is important for determining treatment, but can only be confirmed by molecular genetic testing. We aimed to compare the regional distribution of confirmed MODY cases in the UK and to estimate the minimum prevalence.This article is freely available via Open Access. Click on the ‘Additional Link’ above to access the full-text from the publisher’s site.PDA/02/06/098/Department of Health/United Kingdo

A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity.

Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY

Insulin Promoter Factor 1 variation is associated with type 2 diabetes in African Americans

<p>Abstract</p> <p>Background</p> <p>Defective insulin secretion is a key defect in the pathogenesis of type 2 diabetes (T2DM). The β-cell specific transcription factor, insulin promoter factor 1 gene (<it>IPF1</it>), is essential to pancreatic development and the maintenance of β-cell mass. We hypothesized that regulatory or coding variants in <it>IPF1 </it>contribute to defective insulin secretion and thus T2DM.</p> <p>Methods</p> <p>We screened 71 Caucasian and 69 African American individuals for genetic variants in the promoter region, three highly conserved upstream regulatory sequences (PH1, PH2 and PH3), the human β-cell specific enhancer, and the two exons with adjacent introns. We tested for an association of each variant with T2DM Caucasians (192 cases and 192 controls) and African Americans (341 cases and 186 controls).</p> <p>Results</p> <p>We identified 8 variants in the two populations, including a 3 bp insertion in exon 2 (InsCCG243) in African Americans that resulted in an in-frame proline insertion in the transactivation domain. No variant was associated with T2DM in Caucasians, but polymorphisms at -3766 in the human β-cell enhancer, at -2877 bp in the PH1 domain, and at -108 bp in the promoter region were associated with T2DM in African American subjects (p < 0.01), both individually and as haplotypes (p = 0.01 correcting by permutation test). No SNP altered a binding site for the expected β-cell transcription factors. The rare alleles of InsCCG243 in exon 2 showed a trend to over-representation among African American diabetic subjects (p < 0.1), but this trend was not significant on permutation test.</p> <p>Conculsion</p> <p>The common alleles of regulatory variants in the 5' enhancer and promoter regions of the <it>IPF1 </it>gene increase susceptibility to type 2 diabetes among African American individuals, likely as a result of gene-gene or gene-environment interactions. In contrast, <it>IPF1 </it>is not a cause of type 2 diabetes in Caucasians. A previously described InsCCG243 variant may contribute to diabetes susceptibility in African American individuals, but is of low penetrance.</p