ライフサイエンスコーパス: MODY

1 MODY genes have been localized to chromosomes 7, 12 and

2 MODY is genetically heterogeneous, with 8 distinct MODY

3 maturity-onset diabetes of the young type 2 (MODY-2) were determined by a steady-state kinetic analys

4 maturity-onset diabetes of the young form 3 (MODY 3) and type 2 diabetes.

5 Maturity Onset Diabetes of the Young-type 3 (MODY-3) has been linked to mutations in the transcriptio

6 nced 732 kb of genomic sequence at 8p23 in 6 MODY families unlinked to known MODY genes that showed e

7 In contrast, a MODY variant that occurs in young blacks, termed atypica

8 In summary, we have identified a MODY locus on 8p23 that accounts for diabetes in a subst

9 R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M sub

10 To identify additional MODY loci, we conducted a genome scan in 21 extended U.S

11 n can cause significant effects in afflicted MODY patients.

12 owth factor-beta-inducible early gene 2) and MODY VII (maturity onset diabetes of the young VII), reg

13 on link between ordinary type 2 diabetes and MODY.

14 te complications, such as hypomagnesemia and MODY diabetes.

15 use renal malformations, hypomagnesemia, and MODY.

16 a high affinity promoter element of another MODY gene, HNF1alpha, which reveals the molecular basis

17 for linkage to MODY2 (glucokinase-associated MODY) was observed with either study population.

18 Both MODY groups exhibited glucose intolerance after oral glu

19 associated with a syndrome characterized by MODY and severe, non-diabetic renal disease.

20 in the HNF-3beta gene (HNF3B) may also cause MODY.

21 ear whether or not these mutations can cause MODY.

22 eased levels of HNF-1 alpha per se can cause MODY.

23 Expression of CEL MODY increased endoplasmic reticulum stress, activated t

24 Secretion of CEL MODY was decreased compared with that of CEL14R.

25 In both cell types, CEL MODY formed intracellular aggregates.

26 ld find structural pancreatic changes in CEL-MODY subjects during the course of diabetes development.

27 These findings show that subjects with CEL-MODY develop multiple pancreatic cysts by the time they

28 se can often allow the clinician to diagnose MODY.

29 s genetically heterogeneous, with 8 distinct MODY genes identified to date and more believed to exist

30 The eight MODY-2 mutations studied were Ala53Ser, Val367Met, Gly80

31 3, we conducted a genome scan in 13 extended MODY families in which diabetes segregates with an HNF-1

32 Five molecular causes for MODY have been identified: mutations in four transcripti

33 fraction of individuals as being at risk for MODY or other Mendelian diseases.

34 Although testing for MODY mutations is only available in research laboratorie

35 We studied 178 U.K. and French MODY family members, including 45 GCK mutation carriers

36 with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-alpha (HNF4A

37 assays and replicated in a cohort of 11 GCK-MODY patients.

38 Analysis of four GCK-MODY patients revealed a metabolite pattern similar to t

39 y-onset diabetes of the young (MODY)2 or GCK-MODY.

40 It has therefore been suggested that GCK-MODY represents a metabolically compensated condition, b

41 Our results show that GCK-MODY represents a metabolically normal condition, which

42 ed for mutations in subjects thought to have MODY because of mutations in this gene.

43 genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and No

44 tic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (-5.1

45 s, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic >/

46 DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offere

47 profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical va

48 t sizes reduce the age at diagnosis in HNF1A-MODY.

49 prove the efficiency of a diagnosis of HNF1A-MODY.

50 further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepato

51 a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glyc

52 causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sul

53 ), hepatocyte nuclear factor 4-alpha (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes

54 diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respe

55 aturity-onset diabetes of the young type II (MODY-II) and persistent hypoglycemic hyperinsulinemia of

56 Pdx1 (IPF-1 in humans, which is altered in MODY-4) is essential for pancreas development and mature

57 have localized the genes that are mutated in MODY on human chromosomes 20 (MODY1), 7 (MODY2) and 12 (

58 se-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, c

59 DY genes, suggesting that gene regulation in MODY is more complex than anticipated previously.

60 ear factor (HNF)-1alpha and -1beta result in MODY (maturity-onset diabetes of the young).

61 duals) in which MODY was not caused by known MODY genes.

62 s of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finni

63 sociation with SNPs in five of the six known MODY genes: GCK, HNF1A, HNF1B, NEUROD1, and HNF4A.

64 at 8p23 in 6 MODY families unlinked to known MODY genes that showed evidence of linkage at that locat

65 l proportion of MODY cases unlinked to known MODY genes.

66 of non-insulin-dependent diabetes mellitus, MODY-4.

67 Furthermore, because KLF11 like most MODY-associated transcription factors uses p300, these d

68 ve research, the mechanism by which a mutant MODY gene results in monogenic diabetes is not yet clear

69 Cloning these new MODY genes may offer insights to disease pathways that a

70 HNF-4 alpha gene may cause early-onset NIDDM/MODY in Japanese but they are less common than mutations

71 ted Japanese subjects with early-onset NIDDM/MODY of unknown cause.

72 Another novel MODY locus may be present on 2q37.

73 nts in these six genes explain most cases of MODY, common variants in these same genes contribute ver

74 encoding HNF-4 alpha being another cause of MODY (MODY1).

75 tations in NEUROG3 are not a common cause of MODY in Japanese patients.

76 mutations in HNF3B are not a common cause of MODY in Japanese subjects.

77 ariation in NEUROD4 is not a common cause of MODY in Japanese.

78 lpha gene are a relatively uncommon cause of MODY, and our understanding of the MODY1 form of diabete

79 ssed in the beta-cell are the major cause of MODY, and the phenotype clearly varies with the gene tha

80 most common cause of PND and a rare cause of MODY.

81 panese subjects with a clinical diagnosis of MODY for mutations in HNF3B.

82 panese subjects with a clinical diagnosis of MODY for mutations in the NeuroD4/Math-3/ATH-3 gene (NEU

83 The diagnosis of MODY has implications for the clinical management of the

84 -/-) mice might be related to dysfunction of MODY-related transcription factors, we measured the expr

85 The predicted effects of MODY mutations have been tested by a set of biochemical

86 onset of overt hyperglycemia in this form of MODY.

87 cade might be responsible for other forms of MODY and/or late-onset type 2 diabetes.

88 poglycemia with a positive family history of MODY.

89 epatic GK contribute to the hyperglycemia of MODY-2.

90 fer new insights into the pathophysiology of MODY that may, in turn, increase our understanding of th

91 for diabetes in a substantial proportion of MODY cases unlinked to known MODY genes.

92 e as invaluable tools to dissect the role of MODY genes in the development of pancreas and islet cell

93 Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data

94 ls (hiPSCs) from patients with five types of MODY: MODY1 (HNF4A), MODY2 (GCK), MODY3 (HNF1A), MODY5 (

95 C), was found in a heterozygous state in one MODY subject and two nondiabetic subjects.

96 DM: maturity-onset diabetes of the young, or MODY (which is due to glucokinase mutations in about 40%

97 in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-

98 udies, which show that, in contrast to other MODY gene products, the subtle disruption of HNF4alpha m

99 79-125, P = 2 x 10(-21)) for diabetes in our MODY cohort compared with control subjects.

100 Overall, our MODY-hiPSCs serve as invaluable tools to dissect the rol

101 eal similar examples of rare, low-penetrance MODY mutations.

102 truncating variants cause reduced penetrance MODY.

103 Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer

104 t diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant f

105 data suggest that common variants in several MODY genes play a modest role in type 2 diabetes suscept

106 G1117E), each of which was found in a single MODY family.

107 Six MODY genes have been discovered to date.

108 s and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chro

109 tein truncating variants are enriched in the MODY discovery cohort compared to the European control p

110 ts have been conflicting and coverage of the MODY genes has been incomplete.

111 ed their role as potential moderators of the MODY phenotype.

112 together, these results illustrate that the MODY-2 phenotype may be linked not only to kinetic alter

113 D13787 and D13S252, in the region where the MODY-4 gene has previously been mapped.

114 These MODY-hiPSCs morphologically resemble human pluripotent s

115 he regulation of expression of each of these MODY genes, suggesting that mutations in the HNF-3beta g

116 to a noninsulin requiring course similar to MODY in whites.

117 ant pathogenetic differences between the two MODY forms.

118 ierarchical regulatory cascade for these two MODY genes, suggesting that gene regulation in MODY is m

119 uncover the molecular mechanisms underlying MODY.

120 enced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabete

121 youth with a deletion mutation in the VNTR (MODY)).

122 es, for a total of 237 individuals) in which MODY was not caused by known MODY genes.

123 tein truncating variants are associated with MODY with reduced penetrance.Maturity-onset diabetes of

124 polymorphisms that were not associated with MODY, including five in the 5'-untranslated region (UTR)

125 polymorphisms that were not associated with MODY, including one in the promoter region (-213A/G), tw

126 These polymorphisms were not associated with MODY, thereby suggesting that mutations in NEUROG3 are n

127 gene promoter has also been associated with MODY.

128 ose clinical presentation is compatible with MODY.

129 on of the HNF-1 alpha gene cosegregates with MODY.

130 own about incretin function in patients with MODY, we studied the incretin effect and hormone respons

131 inical studies have shown that subjects with MODY due to mutations in glucokinase have elevated fasti

132 s gene have been identified in subjects with MODY.

133 nctional characterization of variants within MODY genes may overcome the limitations of bioinformatic

134 of proven maturity-onset diabetes of young (MODY) (n = 805) and T1D (n = 1,963) (receiver operating

135 Type 1 maturity onset diabetes of young (MODY), which is characterized by abnormal glucose-mediat

136 s with maturity-onset diabetes of the young (MODY) and in some individuals with type 2 diabetes.

137 ion of maturity-onset diabetes of the young (MODY) cases in the U.S.

138 itting maturity-onset diabetes of the young (MODY) criteria was 63% HNF-1alpha, 2% HNF-4alpha, 0% IPF

139 ion of maturity-onset diabetes of the young (MODY) genes to NIDDM susceptibility in African-American

140 known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diab

141 embles maturity-onset diabetes of the young (MODY) in many respects.

142 es for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003).

143 Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous subg

144 Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic disorder

145 isease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of n

146 turity-onset diabetes mellitus of the young (MODY) is a human genetic syndrome most commonly due to m

147 (CEL) maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes and pancreatic exo

148 Maturity-onset diabetes of the young (MODY) is a subtype of diabetes defined by an autosomal d

149 Maturity-onset diabetes of the young (MODY) is a subtype of diabetes defined by an autosomal p

150 Maturity onset diabetes of the young (MODY) is an autosomal dominant disease.

151 trance.Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes.

152 es for maturity-onset diabetes of the young (MODY) may confer susceptibility to type 2 diabetes, but

153 d with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and t

154 rt the maturity-onset diabetes of the young (MODY) phenotype in humans and mitochondrial DNA mutation

155 orm of maturity-onset diabetes of the young (MODY) results from mutations in a gene, designated MODY3

156 cause maturity-onset diabetes of the young (MODY) type 3.

157 al for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked gly

158 use of maturity-onset diabetes of the young (MODY), a form of non-insulin-dependent diabetes mellitus

159 Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NI

160 s with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes

161 ics of maturity onset diabetes of the young (MODY), regardless of serum Mg(2+) levels.

162 orm of maturity-onset diabetes of the young (MODY), type 5 (MODY5).

163 ses of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology an

164 cause maturity-onset diabetes of the young (MODY), which is characterized by autosomal-dominant inhe

165 a, and maturity onset diabetes of the young (MODY).

166 s with maturity-onset diabetes of the young (MODY).

167 ses of maturity-onset diabetes of the young (MODY).

168 ne for maturity onset diabetes of the young (MODY).

169 ved in maturity onset diabetes of the young (MODY).

170 idated maturity-onset diabetes of the young (MODY).

171 use of maturity-onset diabetes of the young (MODY).

172 use of maturity-onset diabetes of the young (MODY).

173 cause maturity-onset diabetes of the young (MODY).

174 own as maturity onset diabetes of the young (MODY).

175 ult in maturity-onset diabetes of the young (MODY).

176 termed maturity-onset diabetes of the young (MODY)2 or GCK-MODY.

177 betes (maturity-onset diabetes of the young [MODY]), MODY3 and MODY1, which are characterized by impa

178 betes (maturity-onset diabetes of the young [MODY]).

179 digree/maturity-onset diabetes of the young [MODY]-1) have diminished insulin and glucagon secretory

180 tions (maturity-onset diabetes of the young [MODY]-3) is characterized by impaired insulin secretion.

181 Maturity onset diabetes of youth (MODY) occurs in children, adolescents and young adults a