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 able maturity-onset diabetes of the young 1 (MODY-1), supporting the therapeutic potential of HNF4 ac

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

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

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

7 nosis' (BDD) population study (n = 46 (1.3%) MODY (HNF1A, HNF4A, GCK)).

8 large published pedigrees per gene (n < 3), MODY-associated variants showed only modest cosegregatio

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

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

11 isions on who to test, we aimed to develop a MODY probability calculator for paediatric cases at the

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

13 den testing to test gene-level evidence in a MODY cohort (n = 1,227) compared with a control populati

14 nts in APPL1 and WFS1 were not enriched in a MODY cohort (n = 2,571) compared with population control

15 cating variants (PTV) were not enriched in a MODY cohort compared with the UK Biobank population (PTV

16 ants in APPL1 and WFS1 are not enriched in a MODY cohort, but those in PDX1 and NEUROD1 are, at a lev

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

18 ucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiti

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

20 n can cause significant effects in afflicted MODY patients.

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

22 on link between ordinary type 2 diabetes and MODY.

23 te complications, such as hypomagnesemia and MODY diabetes.

24 use renal malformations, hypomagnesemia, and MODY.

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

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

27 Both MODY groups exhibited glucose intolerance after oral glu

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

29 of the variants that separated known causal MODY variants from benign and type 2 diabetes risk varia

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

31 ear whether or not these mutations can cause MODY.

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

33 DY11), KLF11 (MODY7), and PAX4 (MODY9) cause MODY.

34 scores >9), and are all too common to cause MODY (minor allele frequency >4.95 x 10-5).

35 ants in PDX1, NEUROD1, APPL1, and WFS1 cause MODY.

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

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

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

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

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

41 se can often allow the clinician to diagnose MODY.

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

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

44 large MODY cohort, alongside two established MODY genes as positive controls (HNF1A-high penetrance,

45 me of diabetes diagnosis, when the existing "MODY calculator" cannot be used.

46 3, we conducted a genome scan in 13 extended MODY families in which diabetes segregates with an HNF-1

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

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

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

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

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

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

53 aring insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by compari

54 sposal similarly in control subjects and GCK-MODY but was 29% and 22% less effective in type 1 diabet

55 l insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type

56 s similarly between control subjects and GCK-MODY, but to a lesser extent for type 1 diabetes.

57 milarly elevated for type 1 diabetes and GCK-MODY.

58 ibution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes.

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

60 erinsulinemia and hyperglycemia matching GCK-MODY).

61 of the young (MODY) and PND (HNF4A-MODY, GCK-MODY, HNF1A-MODY, HNF1B-MODY, INS-MODY, or INS-PND; n =

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

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

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

65 Patients with GCK-MODY are frequently misdiagnosed and treated unnecessari

66 CK-maturity-onset diabetes of the young (GCK-MODY), collectively affecting up to 10 million people wo

67 se-maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabe

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

69 nset diabetes of the young 3 (MODY3 or HNF1A MODY), a disease characterized by dominant inheritance,

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

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

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

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

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

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

76 (MODY) and PND (HNF4A-MODY, GCK-MODY, HNF1A-MODY, HNF1B-MODY, INS-MODY, or INS-PND; n = 37), and com

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

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

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

80 ctionally damaging HNF1A variants with HNF1A-MODY and type 2 diabetes is well established owing to ro

81 PND (HNF4A-MODY, GCK-MODY, HNF1A-MODY, HNF1B-MODY, INS-MODY, or INS-PND; n = 37), and compared their

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

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

84 disturbed in Hnf4a knockout liver and HNF4A-MODY diabetic model cells.

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

86 ty-onset diabetes of the young (MODY1; HNF4A-MODY), rare phenotypes also include hyperinsulinemic hyp

87 diabetes of the young (MODY) and PND (HNF4A-MODY, GCK-MODY, HNF1A-MODY, HNF1B-MODY, INS-MODY, or INS

88 ons are important to better understand HNF4A-MODY genotype-phenotype correlations, as our data suppor

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

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

91 DX1, APPL1, and WFS1 have been implicated in MODY, but strong genetic evidence supporting causality i

92 They should not be included in MODY diagnostic genetic testing.

93 PDX1 and NEUROD1 should be included in MODY gene panels, while heterozygous APPL1 and WFS1 vari

94 for causality and should not be included in MODY testing panels.

95 an be used in precision diabetes medicine in MODY.

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

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

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

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

100 -MODY, GCK-MODY, HNF1A-MODY, HNF1B-MODY, INS-MODY, or INS-PND; n = 37), and compared their pancreas v

101 most prevalent form of monogenic diabetes is MODY, which may account for 0.5-5% of patients diagnosed

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

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

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

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

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

107 performed gene-level burden tests in a large MODY cohort, alongside two established MODY genes as pos

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

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

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

111 to re-evaluate genetic diagnoses in national MODY diagnostic registries.

112 examine the role of ONECUT1 variants in NDM, MODY, and type 2 diabetes in large international cohorts

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

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

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

116 F1A variants identified in the UK and Norway MODY diagnostic registries, respectively.

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

118 own to 4% of the cohort, and detected 96% of MODY cases (PPV = 31%).

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

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

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

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

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

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

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

126 ot support BLK, KLF11, or PAX4 as a cause of MODY.

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

128 rison we analyzed well-established causes of MODY, HNF1A, and HNF4A.

129 EUROD1 and PDX1 are low-penetrance causes of MODY, while those in APPL1 and WFS1 lack robust genetic

130 variants should not be reported as causes of MODY.

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

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

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

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

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

136 onset of overt hyperglycemia in this form of MODY.

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

138 poglycemia with a positive family history of MODY.

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

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

141 a were significant independent predictors of MODY.

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

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

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

145 mong 484 individuals clinically suspected of MODY, in whom all known genes had been excluded.

146 1,280 patients with a clinical suspicion of MODY who were not suspected of having monogenic syndromi

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

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

149 Most patients with neonatal diabetes or MODY have autosomal dominant diabetes.

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

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

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

153 79-125, P = 2 x 10(-21)) for diabetes in our MODY cohort compared with control subjects.

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

155 D1 are, at a level similar to low-penetrance MODY genes.

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

157 truncating variants cause reduced penetrance MODY.

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

159 The first reported MODY-associated variants in NEUROD1, PDX1, APPL1, and WF

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

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

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

163 Six MODY genes have been discovered to date.

164 How frequently patients with suspected MODY have a mutation in a monogenic syndromic diabetes g

165 routinely tested in patients with suspected MODY who do not have typical features of a genetic syndr

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

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

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

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

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

171 Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose h

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

173 These MODY-hiPSCs morphologically resemble human pluripotent s

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

175 This MODY calculator for paediatric patients at time of diabe

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

177 ant pathogenetic differences between the two MODY forms.

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

179 uncover the molecular mechanisms underlying MODY.

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

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

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

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

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

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

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

187 gene promoter has also been associated with MODY.

188 homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation

189 ose clinical presentation is compatible with MODY.

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

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

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

193 s gene have been identified in subjects with MODY.

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

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

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

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

198 luding maturity-onset diabetes of the young (MODY) and PND (HNF4A-MODY, GCK-MODY, HNF1A-MODY, HNF1B-M

199 eases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs).

200 betes, maturity-onset diabetes of the young (MODY) and various diabetes-associated syndromes.

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

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

203 ons in maturity-onset diabetes of the young (MODY) genes that predominantly result in isolated diabet

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

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

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

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

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

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

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

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

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

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

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

215 Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes witho

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

217 Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of monogenic diabete

218 sis of maturity-onset diabetes of the young (MODY) is critical for personalized treatment.

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

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

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

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

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

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

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

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

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

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

229 cause maturity-onset diabetes of the young (MODY), increase type 2 diabetes risk, or be benign.

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

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

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

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

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

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

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

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

238 ssibly maturity-onset diabetes of the young (MODY).

239 sis of maturity-onset diabetes of the young (MODY).

240 d with maturity-onset diabetes of the young (MODY).

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

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

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

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

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

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

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

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

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

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

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

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

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