Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy.

Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy. Research Abstract Details 

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Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy. Abstract Text:

Masumi Kamiyama,Masaaki Kobayashi,Shin-Ichi Araki,Aritoshi Iida,Tatsuhiko Tsunoda,Koichi Kawai,Masahito Imanishi,Makoto Nomura,Tetsuya Babazono,Yasuhiko Iwamoto,Atsunori Kashiwagi,Kohei Kaku,Ryuzou Kawamori,Daniel P K Ng,Torben Hansen,Peter Gaede,Oluf Pedersen,Yusuke Nakamura,Shiro Maeda,Masumi Kamiyama,Masaaki Kobayashi,Shin-ichi Araki,Aritoshi Iida,Tatsuhiko Tsunoda,Koichi Kawai,Masahito Imanishi,Makoto Nomura,Tetsuya Babazono,Yasuhiko Iwamoto,Atsunori Kashiwagi,Kohei Kaku,Ryuzou Kawamori,Daniel P K Ng,Torben Hansen,Peter Gaede,Oluf Pedersen,Yusuke Nakamura,Shiro Maeda,

Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin delta (NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3' UTR of NCALD (rs1131863: exon 4 +1340 A vs. G, P = 0.00004, odds ratio = 1.59, 95% CI 1.27-1.98). We also discovered two other SNPs in exon 4 of this gene (+999 T/A, +1307 A/G) that showed absolute linkage disequilibrium to the landmark SNP. Subsequent in vitro functional analysis revealed that synthetic mRNA corresponding to the disease susceptible haplotype (exon 4 +1340 G, +1307 G, +999 A) was degraded faster than mRNA corresponding to the major haplotype (exon 4 +1340 A, +1307 A, +999 T), and allelic mRNA expression of the disease susceptibility allele was significantly lower than that of the major allele in normal kidney tissues. In an experiment using a short interfering RNA targeting NCALD, we found that silencing of the NCALD led to a considerable enhancement of cell migration, accompanied by a significant reduction in E-cadherin expression, and by an elevation of alpha smooth muscle actin expression in cultured renal proximal tubular epithelial cells. We also identified the association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (A vs. G, P = 0.03, odds ratio = 1.91, 95% CI 1.07-3.42). These results suggest that the NCALD gene is a likely candidate for conferring susceptibility to diabetic nephropathy.

Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy. Publishing Authors By Initials

M Kamiyama,M Kobayashi,S Araki,A Iida,T Tsunoda,K Kawai,M Imanishi,M Nomura,T Babazono,Y Iwamoto,A Kashiwagi,K Kaku,R Kawamori,DP Ng,T Hansen,P Gaede,O Pedersen,Y Nakamura,S Maeda,M Kamiyama,M Kobayashi,S Araki,A Iida,T Tsunoda,K Kawai,M Imanishi,M Nomura,T Babazono,Y Iwamoto,A Kashiwagi,K Kaku,R Kawamori,DP Ng,T Hansen,P Gaede,O Pedersen,Y Nakamura,S Maeda,

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Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Human genetics

VOLUME: 122

Page Numbers: 397-407

Journal Abbreviation: Hum. Genet.

ISSN: 0340-6717

DAY: 2

MONTH: 08

YEAR: 2007

Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy. Information

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LANGUAGE: eng

NlmUniqueID: 7613873

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Grant and Affiliation Information for Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy.

AFFILIATION: Laboratory for Diabetic Nephropathy, SNP Research Centre, Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan, smaeda@src.riken.jp.

Country: Germany

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MEDLINETA: Hum Genet

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