Andrew Hattersley

Publications of Andrew Hattersley

• KCNJ11 activating mutations cause both transient and permanent neonatal diabetes mellitus in Cypriot patients.

  Authors: Yiannis S Ioannou, Sian Ellard, Andrew Hattersley, Nicos Skordis

  Pediatric diabetes. 03/2011; 12(2):133-7.

  Heterozygous mutations of the KCNJ11 gene encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (K(ATP) channel) of the pancreatic β-cell cause diabetes in about 30-60% of all permanentHeterozygous mutations of the KCNJ11 gene encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (K(ATP) channel) of the pancreatic β-cell cause diabetes in about 30-60% of all permanent neonatal diabetes mellitus cases diagnosed before 6 months of age. The K(ATP) channel plays an essential role in the regulation of the electrical status of the membrane through which the secretion of insulin is activated. Transient neonatal diabetes mellitus due to KCNJ11 mutations is less frequent than abnormalities affecting the imprinted region of chromosome 6q24. We studied the genetic basis of two Cypriot patients who developed diabetes before 6 months of age. They both carried mutations of the KCNJ11 gene. The R201H mutation was identified in a patient who developed hyperglycemia and ketoacidosis at the age of 40 d and was successfully transferred to sulphonylureas which activate the channel through an ATP independent route. The R50Q mutation was identified in a child diagnosed at day 45 after birth with remission of his diabetes at 9 months of age. The same defect was identified both in his asymptomatic mother and the recently diagnosed 'type 2' diabetic maternal grandmother. The remission-relapse mechanism in cases of transient neonatal diabetes is not known. Nevertheless, it is possible that the residue of the mutation within the Kir6.2 molecule is associated with the sensitivity to ATP reflecting to the severity of the diabetic phenotype.

• A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.

  Authors: Peter N Taylor, Vijay Panicker, Adrian Sayers, Beverley Shields, Ahmed Iqbal, Alexandra P Bremner, John P Beilby, Peter J Leedman, Andrew T Hattersley, Bijay Vaidya, Timothy Frayling, Jonathan Evans, Jonathan H Tobias, Nicholas J Timpson, John P Walsh, Colin M Dayan

  European journal of endocrinology / European Federation of Endocrine Societies. 02/2011; 164(5):773-80.

  Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not beenCommon variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T(4)). Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T(4)). Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T(3)), and T(4) levels. Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64 × 10(-10) 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T(4) (P=0.023, -0.07 s.d./allele, 95% CI -0.137, -0.01), no association was seen with free T(3) (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T(4) in 1981 (-0.068 s.d./allele, 95% CI -0.167, 0.031) and 1994 (-0.07 s.d./allele, 95% CI -0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T(4). Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T(4) levels that are consistent over time and lost in individuals on l-T(4). These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid.

• Interaction between mutations in the slide helix of Kir6.2 associated with neonatal diabetes and neurological symptoms.

  Authors: Roope Männikkö, Craig Jefferies, Sarah E Flanagan, Andrew Hattersley, Sian Ellard, Frances M Ashcroft

  Human molecular genetics. 12/2009;

  K(ATP) channels regulate insulin secretion from pancreatic beta-cells. Gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause neonatal diabetes. We reportK(ATP) channels regulate insulin secretion from pancreatic beta-cells. Gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause neonatal diabetes. We report two novel mutations on the same haplotype (cis), F60Y and V64L, in the slide helix of Kir6.2 in a patient with neonatal diabetes, developmental delay and epilepsy. Functional analysis revealed the F60Y mutation increases the intrinsic channel open probability (Po((0))), thereby indirectly producing a marked decrease in channel inhibition by ATP and an increase in whole-cell K(ATP) currents. When expressed alone, the V64L mutation caused a small reduction in apparent ATP inhibition, by enhancing the ability of MgATP to stimulate channel activity. The V64L mutation also ameliorated the deleterious effects on the F60Y mutation when it was expressed on the same (but not a different) subunit. These data indicate that F60Y is the pathogenic mutation and reveal that interactions between slide helix residues can influence K(ATP) channel gating.

• Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes.

  Authors: Janniche Torsvik, Stefan Johansson, Anders Johansen, Jakob Ek, Jayne Minton, Helge Ræder, Sian Ellard, Andrew Hattersley, Oluf Pedersen, Torben Hansen, Anders Molven, Pål Njølstad

  Human genetics. 09/2009;

  We have previously shown that heterozygous single-base deletions in the carboxyl-ester lipase (CEL) gene cause exocrine and endocrine pancreatic dysfunction in two multigenerational families. TheseWe have previously shown that heterozygous single-base deletions in the carboxyl-ester lipase (CEL) gene cause exocrine and endocrine pancreatic dysfunction in two multigenerational families. These deletions were found in the first and fourth repeats of a variable number of tandem repeats (VNTR), which has proven challenging to sequence due to high GC-content and considerable length variation. We have therefore developed a screening method consisting of a multiplex PCR followed by fragment analysis. The method detected putative disease-causing insertions and deletions in the proximal repeats of the VNTR, and determined the VNTR-length of each allele. When blindly testing 56 members of the two families with known single-base deletions in the CEL VNTR, the method correctly assessed the mutation carriers. Screening of 241 probands from suspected maturity-onset diabetes of the young (MODY) families negative for mutations in known MODY genes (95 individuals from Denmark and 146 individuals from UK) revealed no deletions in the proximal repeats of the CEL VNTR. However, we found one Danish patient with a short, novel CEL allele containing only three VNTR repeats (normal range 7-23 in healthy controls). This allele co-segregated with diabetes or impaired glucose tolerance in the patient's family as six of seven mutation carriers were affected. We also identified individuals who had three copies of a complete CEL VNTR. In conclusion, the CEL gene is highly polymorphic, but mutations in CEL are likely to be a rare cause of monogenic diabetes.

• Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism.

  Authors: Kenju Shimomura, Sarah E Flanagan, Brittany Zadek, Mark Lethby, Lejla Zubcevic, Christophe A J Girard, Oliver Petz, Roope Mannikko, Ritika R Kapoor, Khalid Hussain, Mars Skae, Peter Clayton, Andrew Hattersley, Sian Ellard, Frances M Ashcroft

  EMBO molecular medicine. 06/2009; 1(3):166-77.

  K(ATP) channels regulate insulin secretion from pancreatic beta-cells. Loss- and gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause hyperinsulinism ofK(ATP) channels regulate insulin secretion from pancreatic beta-cells. Loss- and gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause hyperinsulinism of infancy and neonatal diabetes, respectively. We report two novel mutations in the gating loop of Kir6.2 which cause neonatal diabetes with developmental delay (T293N) and hyperinsulinism (T294M). These mutations increase (T293N) or decrease (T294M) whole-cell K(ATP) currents, accounting for the different clinical phenotypes. The T293N mutation increases the intrinsic channel open probability (Po((0))), thereby indirectly decreasing channel inhibition by ATP and increasing whole-cell currents. T294M channels exhibit a dramatically reduced Po((0)) in the homozygous but not in the pseudo-heterozygous state. Unlike wild-type channels, hetT294M channels were activated by MgADP in the absence but not in the presence of MgATP; however, they are activated by MgGDP in both the absence and presence of MgGTP. These mutations demonstrate the importance of the gating loop of Kir channels in regulating Po((0)) and further suggest that Mg-nucleotide interaction with SUR1 may reduce ATP inhibition at Kir6.2.

• FTO gene variation and measures of body mass in an African population

  Authors: Branwen Hennig, Anthony Fulford, Giorgio Sirugo, Pura Rayco-Solon, Andrew Hattersley, Timothy Frayling, Andrew Prentice

  BMC Medical Genetics. 01/2009;

  Abstract Background Variation in the fat mass and obesity associated ( FTO ) gene has been reproducibly associated with body mass index (BMI) and obesity in populations of White European origin.Abstract Background Variation in the fat mass and obesity associated ( FTO ) gene has been reproducibly associated with body mass index (BMI) and obesity in populations of White European origin. Data from Asians and African-Americans is less conclusive. Methods We assessed the effect of 16 FTO polymorphisms on body mass in a large population of predominantly lean Gambians (N_max2208) participating in a long-term surveillance program providing contemporary and early-life anthropometric measurements. Results Sixteen FTO tagSNPs screened here, including several associated with BMI in Europeans, were not associated with birth weight (BWT), early weight gain in 1–2 year olds, BMI in adults (≥ 18 y), or weight-for-height (WFH) z-score across all ages. No association was seen between genotype and WFH z-score or other measures of body mass. The confidence limits indicate that the effect size for WFH z-score never exceeded 0.17 units per allele copy for any SNP (excluding the three SNPs with allele < 15%). with much the lowest allele frequency. The confidence interval of the effect size for rs9939609 did not overlap that reported previously in Europeans. Conclusion To our knowledge this is the first study of FTO gene variation in a well-characterised African population. Our results suggest that FTO gene variation does not influence measures of body mass in Gambians living a traditional lifestyle, or has a smaller effect than that detected in Europeans. These findings are not directly comparable to results from previous studies in African-Americans due to differences in study design and analysis. It is also possible that any effect of FTO genotype on body mass is of limited relevance in a lean population where little excess food is available, compared to similar ethnic populations where food supply is plentiful.

• Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C.

  Authors: Julia Rankin, Michaela Auer-Grumbach, Warwick Bagg, Kevin Colclough, Thuy Duong Nguyen, Jane Fenton-May, Andrew Hattersley, Judith Hudson, Philip Jardine, Dragana Josifova, Cheryl Longman, Robert McWilliam, Katharine Owen, Mark Walker, Manfred Wehnert, Sian Ellard

  American journal of medical genetics. Part A. 06/2008; 146A(12):1530-42.

  Mutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, DunniganMutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibulo acral dysplasia, Hutchinson Gilford progeria syndrome, restrictive dermopathy and autosomal recessive Charcot Marie Tooth type 2. The c.1930C > T (R644C) missense mutation has previously been reported in eight unrelated patients with variable features including left ventricular hypertrophy, limb girdle muscle weakness, dilated cardiomyopathy and atypical progeria. Here we report on the details of nine additional patients in eight families with this mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance, Patient 1 having in addition focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, Patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular non-compaction, Patient 5 with severe scoliosis and contractures, Patient 6 with limb girdle weakness and Patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 are brothers with proximal weakness and contractures. Nonpenetrance was observed frequently in first degree relatives. This report provides further evidence of the extreme phenotypic diversity and low penetrance associated with the R644C mutation. Possible explanations for these observations are discussed.

• The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians

  Authors: Rachel Freathy, Michael Weedon, David Melzer, Beverley Shields, Graham Hitman, Mark Walker, Mark McCarthy, Andrew Hattersley, Timothy Frayling

  BMC Medical Genetics. 01/2006;

  Abstract Background Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO ( KL ) gene isAbstract Background Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO ( KL ) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. Methods We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. Results Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84–1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. Conclusion This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study.

• Assessing newborn body composition using principal components analysis: differences in the determinants of fat and skeletal size

  Authors: Beverley Shields, Bridget Knight, Roy Powell, Andrew Hattersley, David Wright

  BMC Pediatrics. 01/2006;

  Abstract Background Birth weight is a composite of skeletal size and soft tissue. These components are likely to have different growth patterns. The aim of this paper is to investigate theAbstract Background Birth weight is a composite of skeletal size and soft tissue. These components are likely to have different growth patterns. The aim of this paper is to investigate the association between established determinants of birth weight and these separate components. Methods Weight, length, crown-rump, knee-heel, head circumference, arm circumference, and skinfold thicknesses were measured at birth in 699 healthy, term, UK babies recruited as part of the Exeter Family Study of Childhood Health. Corresponding measurements were taken on both parents. Principal components analysis with varimax rotation was used to reduce these measurements to two independent components each for mother, father and baby: one highly correlated with measures of fat, the other with skeletal size. Results Gestational age was significantly related to skeletal size, in both boys and girls (r = 0.41 and 0.52), but not fat. Skeletal size at birth was also associated with parental skeletal size (maternal: r = 0.24 (boys), r = 0.39 (girls) ; paternal: r = 0.16 (boys), r = 0.25 (girls)), and maternal smoking (0.4 SD reduction in boys, 0.6 SD reduction in girls). Fat was associated with parity (first borns smaller by 0.45 SD in boys; 0.31 SD in girls), maternal glucose (r = 0.18 (boys); r = 0.27 (girls)) and maternal fat (r = 0.16 (boys); r = 0.36 (girls)). Conclusion Principal components analysis with varimax rotation provides a useful method for reducing birth weight to two more meaningful components: skeletal size and fat. These components have different associations with known determinants of birth weight, suggesting fat and skeletal size may have different regulatory mechanisms, which would be important to consider when studying the associations of birth weight with later adult disease.

• A study of association between common variation in the growth hormone-chorionic somatomammotropin hormone gene cluster and adult fasting insulin in a UK Caucasian population

  Authors: Rachel Freathy, Simon Mitchell, Beatrice Knight, Beverley Shields, Michael Weedon, Andrew Hattersley, Timothy Frayling

  Journal of Negative Results in Biomedicine. 01/2006;

  Abstract Background Reduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionicAbstract Background Reduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionic somatomammotropin hormone gene cluster was recently associated with increases in adult fasting insulin of approximately 23 pmol/l for TT homozygote males compared to D1D1 or D2D2 homozygotes ( P = 0.001 and 0.009; n = 206 and 92, respectively), but not for females. TT males additionally had a 547-g lower weight at 1 year ( n = 270; P = 0.008) than D2D2 males. We sought to replicate these data in healthy UK Caucasian subjects. We genotyped 1396 subjects (fathers, mothers and children) from a consecutive birth study for the CSH1.01 marker and analysed genotypes for association with 1-year weight in boys and fasting insulin in fathers. Results We found no evidence for association of CSH1.01 genotype with adult male fasting insulin concentrations (TT/D1D1 P = 0.38; TT/D2D2 P = 0.18) or weight at 1 year in boys (TT/D1D1 P = 0.76; TT/D2D2 P = 0.85). For fasting insulin, our data can exclude the previously observed effect sizes as the 95 % confidence intervals for the differences observed in our study exclude increases in fasting insulin of 9.0 and 12.6 pmol/l for TT relative to D1D1 and D2D2 homozygotes, respectively. Whilst we have fewer data on boys' 1-year weight than the original study, our data can exclude a reduction in 1-year weight greater than 557 g for TT relative to D2D2 homozygotes. Conclusion We have not found association of the CSH1.01 genotype with fasting insulin or weight at 1 year. We conclude that the original study is likely to have over-estimated the effect size for fasting insulin, or that the difference in results reflects the younger age of subjects in this study relative to those in the previous study.

• Allelic drop-out may occur with a primer binding site polymorphism for the commonly used RFLP assay for the -1131T>C polymorphism of the Apolipoprotein AV gene

  Authors: Kirsten Ward, Sian Ellard, Chittaranjan Yajnik, Timothy Frayling, Andrew Hattersley, Prathyusha Venigalla, Giriraj Chandak

  Lipids in Health and Disease. 01/2006;

  Abstract Apolipoprotein AV (ApoAV) gene variant, -1131T>C, is associated with increased triglyceride concentrations in all ethnic groups studied. An MseI based RFLP analysis is the most commonlyAbstract Apolipoprotein AV (ApoAV) gene variant, -1131T>C, is associated with increased triglyceride concentrations in all ethnic groups studied. An MseI based RFLP analysis is the most commonly used method for genotyping this SNP. We genotyped a large cohort comprising 1185 Asian Indians and 173 UK Caucasians for -1131T>C using an ARMS-PCR based tetra-primer method. For quality control, we re-genotyped approximately 10% random samples from this cohort utilizing the MseI RFLP, which showed a 2.9% (3/102) genotyping error rate between the two methods. To investigate further, we sequenced the 900 bp region around the -1131T>C polymorphism in 25 Asian Indians and 15 UK Caucasians and found a number of polymorphisms including the -987C>T polymorphism. Further analysis of the -987C>T SNP showed a higher rare allele frequency of 0.23 in Asian Indians (n = 158) compared to 0.09 in the UK Caucasians (n = 157). This SNP is located 4 bp from the 3' end of the RFLP forward primer and is in weak linkage disequilibrium with -1131T>C variant (r²= 0.084 and D' = 1). Repeated RFLP analysis of seven subjects heterozygous for -987C>T (seven times), showed discordant results with the sequence at -1131T>C SNP nearly one third (15/49) of the time. We conclude that presence of -987C>T polymorphism in the forward primer of the MseI RFLP assay may lead to allelic drop-out and generate unforeseen errors in genotyping the -1131T>C polymorphism. Our results also emphasise the need for careful quality control in all molecular genetic studies, particularly while transferring genotyping methods between various ethnic groups.

• Genetic variants in Apolipoprotein AV alter triglyceride concentrations in pregnancy

  Authors: Kirsten Ward, Beverley Shields, Beatrice Knight, Maurice Salzmann, Andrew Hattersley, Timothy Frayling

  Lipids in Health and Disease. 01/2003;

  Abstract Background Triglyceride concentrations are raised in pregnancy and are considered a key fetal fuel. Several gene variants are known to alter triglyceride concentrations, including those inAbstract Background Triglyceride concentrations are raised in pregnancy and are considered a key fetal fuel. Several gene variants are known to alter triglyceride concentrations, including those in the Apolipoprotein E ( ApoE ), Lipoprotein Lipase ( LPL ), and most recently, the Apolipoprotein AV ( ApoAV ) gene. However, less is known about how variants in these genes alter triglyceride concentrations in pregnancy or affect fetal growth. We aimed to determine the effect of the recently identified ApoAV gene on triglycerides in pregnancy and fetal growth. We assessed the role of two ApoAV haplotypes, defined by the C and W alleles of the -1131T>C and S19W polymorphisms, in 483 pregnant women and their offspring from the Exeter Family Study of Childhood Health. Results The -1131T>C and S19W variants have rare allele frequencies of 6.7% and 4.9% and are present in 13.4% and 9.7% of subjects respectively. In carriers of the -1131C and 19W alleles triglyceride concentrations were raised by 11.0% (1.98 mmol/ l(1.92 – 2.04) to 2.20 mmol/l (2.01 – 2.42), p = 0.035; and 16.2% (1.97 mmol/l (1.91 – 2.03) to 2.29 mmol/l (2.12 – 2.48), p < 0.001 respectively. There is nominally significant evidence that the -1131T>C variant is having an effect on maternal height (164.9 cm (164.3 – 165.5) to 167.0 cm (165.2 – 168.8), p = 0.029). There was no evidence that ApoAV genotype alters any other anthropometric measurements or biochemistries such as High Density Lipoprotein Cholesterol (HDL-C) or Low Density Lipoprotein Cholesterol (LDL-C). There is nominally significant evidence that the presence of a maternal -1131C variant alters fetal birth length (50.2 cm (50.0 – 50.4) to 50.9 cm (50.3 – 51.4), p = 0.022), and fetal birth crown-rump length (34.0 cm (33.8 – 34.1) to 34.5 cm (34.1 – 35.0), p = 0.023). There is no evidence that ApoAV genotype alters fetal birth weight or other fetal growth measurements. Conclusion In conclusion variation in the ApoAV gene raises triglyceride concentrations in pregnancy, as well as normolipaemic states and there is preliminary evidence that it alters fetal growth parameters.

• Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type 1.

  Authors: Jeremy J O Turner, Poloko D Leotlela, Anna A J Pannett, Simon A Forbes, J H Duncan Bassett, Brian Harding, Paul T Christie, David Bowen-Jones, Sian Ellard, Andrew Hattersley, Charles E Jackson, Richard Pope, Oliver W Quarrell, Richard Trembath, Rajesh V Thakker

  The Journal of clinical endocrinology and metabolism. 06/2002; 87(6):2688-93.

  MEN1 is an autosomal dominant disorder characterized by parathyroid, pituitary, and pancreatic tumors. The MEN1 gene is located on chromosome 11q13 and encodes a 610-amino acid protein. MEN1MEN1 is an autosomal dominant disorder characterized by parathyroid, pituitary, and pancreatic tumors. The MEN1 gene is located on chromosome 11q13 and encodes a 610-amino acid protein. MEN1 mutations are of diverse types and are scattered throughout the coding region, such that almost every MEN1 family will have its individual mutation. To further characterize such mutations we ascertained 34 unrelated MEN1 probands and undertook DNA sequence analysis. This identified 17 different mutations in 24 probands (2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletional-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a g-->a transition that resulted in a novel acceptor splice site in intron 4). The intron 4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this intron 4 mutation is the most frequently occurring germline MEN1 mutation ( approximately 10% of all mutations), and together with 5 others at codons 83-84, 118-119, 209-211, 418, and 516, accounts for 36.6% of all mutations, a finding that indicates an approach for identifying the widely diverse MEN1 mutations.

• Increased risk of diabetes in first-degree relatives of young-onset type 2 diabetic patients compared with relatives of those diagnosed later.

  Authors: Katharine Owen, Susan Ayres, Sheila Corbett, Andrew Hattersley

  Diabetes care. 04/2002; 25(3):636-7.