Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

被引：94

作者：

Patel, Kashyap A. ^{[1
]}

Kettunen, Jarno ^{[2
,3
,4
]}

Laakso, Markku ^{[5
,6
]}

Stancakova, Alena ^{[6
]}

Laver, Thomas W. ^{[1
]}

Colclough, Kevin ^{[7
]}

Johnson, Matthew B. ^{[1
]}

Abramowicz, Marc ^{[8
]}

Groop, Leif ^{[9
,10
]}

Miettinen, Paivi J. ^{[11
,12
,13
]}

Shepherd, Maggie H. ^{[1
]}

Flanagan, Sarah E. ^{[1
]}

Ellard, Sian ^{[1
]}

Inagaki, Nobuya ^{[14
]}

Hattersley, Andrew T. ^{[1
]}

Tuomi, Tiinamaija ^{[2
,3
,4
,10
]}

Cnop, Miriam ^{[15
,16
]}

Weedon, Michael N. ^{[1
]}

机构：

[1] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England

[2] Helsinki Univ Hosp, Dept Endocrinol, Abdominal Ctr, Helsinki 00029, Finland

[3] Univ Helsinki, Folkhalsan Res Ctr, FIN-00014 Helsinki, Finland

[4] Univ Helsinki, Res Program Diabet & Obes, Res Programs Unit, FIN-00014 Helsinki, Finland

[5] Kuopio Univ Hosp, Dept Med, Kuopio 70029, Finland

[6] Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio 70029, Finland

[7] Royal Devon & Exeter Natl Hlth Serv Fdn Trust, Dept Mol Genet, Exeter EX2 5DW, Devon, England

[8] Univ Libre Bruxelles, Erasmus Hosp, Dept Genet, IRIBHM, B-1070 Brussels, Belgium

[9] Lund Univ, Skane Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, SE-20502 Malmo, Sweden

[10] Univ Helsinki, FIMM, SF-00100 Helsinki, Finland

[11] Univ Helsinki, Childrens Hosp, Pediat Res Ctr, Helsinki 00029, Finland

[12] Helsinki Univ Hosp, Helsinki 00029, Finland

[13] Univ Helsinki, Fac Med, Mol Neurol & Biomedicum Stem Cell Ctr, Res Programs Unit, FIN-00014 Helsinki, Finland

[14] Kyoto Univ, Grad Sch Med, Dept Diabet Endocrinol & Nutr, Kyoto 6068507, Japan

[15] Univ Libre Bruxelles, Fac Med, ULB Ctr Diabet Res, B-1070 Brussels, Belgium

[16] Univ Libre Bruxelles, Erasmus Hosp, Div Endocrinol, B-1070 Brussels, Belgium

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GASTRIC-INHIBITORY POLYPEPTIDE; AUTOSOMAL RECESSIVE SYNDROME; TYPE-2; DIABETES-MELLITUS; INTESTINAL ATRESIA; SEQUENCE VARIANTS; BETA-CELLS; ONSET; YOUNG; POPULATION; MUTATIONS;

D O I：

10.1038/s41467-017-00895-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 x 10(-4)). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 x 10(-5)) and Finnish (n = 80, odds ratio = 22, P = 1 x 10(-6)) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

引用

页数：8

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