Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.

OBJECTIVE-The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-␣ (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS-We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS-Missense mutations prevailed in the dimerizationand DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1-6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P ϭ 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P ϭ 10 Ϫ4 ). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P ϭ 0.03). MODY3 is characterized by a severe insulin secretion defect, a retained sensitivity to sulfonylureas, a decreased renal threshold for glucose reabsorption, and, in rare families, the occurrence of liver adenomatosis (3-6). CONCLUSIONS-TheseThe clinical expression of MODY3 is highly variable from one family to another or even within the same family (7). HNF1A mutation carriers may be normoglycemic while their siblings may be hyperglycemic at a comparable age (8). Symptoms at diagnosis may be variable. Some patients have metabolic decompensation, while in others diabetes is diagnosed by systematic screening. The severity and the course of insulin secretion defect also vary since approximately one-third of the patients are treated with insulin after 15 years of diabetes duration, whereas others control their diabetes by diet or oral hypoglycemic agents (9).As in other monogenic diseases, this phenotype variability may be explained by environmental and/or additional genetic factors. Two studies have shown that age at diagnosis of diabetes in offspring carrying a HNF1A mutation was lower by 5-10 years when maternal diabetes was diagnosed before pregnancy, suggesting the role of exposure of the fetus to maternal hyperglycemia (10,11). Modifier genetic factors may also modulate the phenotype of the disease. Age at onset of diabetes is partly inheritable within MODY3 families, and putative genetic modifier loci have been mapped but not identified yet (12). In the same vein, it has been recently shown that germ line CYP1B1 Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0859.HNF1A, hepatocyte nuclear factor 1-␣; MODY, maturity-onset diabetes of the young.

No abstract

Relationships between glycaemic control, hypertension, and development of microangiopathy have been well documented in Type 1 (insulin‐dependent) but not in Type 2 (non‐insulin‐dependent) diabetes mellitus. Therefore, we have investigated these relationships in a cohort of 64 Type 2 patients free of retinopathy (by angiofluorography), who were regularly followed until development of retinopathy or for at least 7 years as outpatients. Glycaemic control was assessed by 1 to 4 HbA1 determinations per year. Retinal status was monitored by annual angiofluorography. Nonproliferative retinopathy developed in 14 patients (cumulative incidence at 13 years: 29.8 %) after a mean diabetes duration of 14.3 ± 8.9 years (range 2–27). In multivariate analysis (Cox model), mean HbA1 during follow‐up (p < 0.001), and hypertension at first examination (p = 0.09) were associated with the development of retinopathy, but age, sex, BMI, diabetes duration, smoking, and fasting blood glucose were not. The relative risk for developing retinopathy (RR) was 7.2 (IC 95 %: 1.61–32.4) in patients with a mean HbA1 during follow‐up above the median value of the cohort (8.3 %) compared with patients with HbA1 during follow‐up below this value. RR was 2.5 (IC 0.8–8) in patients with HbA1 at first examination above compared to below the median value (8.4 %). RR was 3.0 (IC 0.9–10) in patients treated for hypertension at baseline compared to those without treatment. A sixfold increase in retinopathy prevalence was observed between patients with mean HbA1 in the highest or lowest quartile of mean HbA1 distribution during follow‐up. This longitudinal study indicates a strong association between long‐term glycaemic control and the development of diabetic retinopathy in Type 2 diabetes. © 1998 John Wiley & Sons, Ltd.