Dunn J S, Mlynarski W M, Pezzolesi M G, Borowiec M, Powers C, Krolewski A S, Doria A
Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Ann Hum Genet. 2006 Sep;70(Pt 5):587-93. doi: 10.1111/j.1469-1809.2005.00248.x.
The product of the PPP1R3B gene (G(L)) is the regulatory subunit of PP1 - a serine/threonine phosphatase involved in the modulation of glycogen synthesis in the liver and skeletal muscle. The PPP1R3B gene is located on chromosome 8p23 in a region that has been linked with type 2 diabetes and maturity-onset diabetes of the young (MODY). We examined whether sequence variants at the PPP1R3B locus are responsible for the linkage with diabetes observed at this location. RT-PCR analysis revealed the existence of two alternative promoters. These and the two exons of this gene were sequenced in the probands of 13 Joslin families showing the strongest evidence of linkage at 8p23. A total of 20 variants were observed: two in the 5' flanking region, one in the intron (9 bp 5' of exon 2), and 17 in the 3' UTR. The intronic variant generated a new acceptor splice site, resulting in an alternative splice variant with a longer 5' UTR. However, neither this nor other variants segregated with diabetes in the 13 'linked' families. Furthermore, allele frequencies were similar in 90 family probands from the Joslin Study and 347 unrelated controls. Thus, genetic variability in the PPP1R3B gene does not appear to contribute to diabetes in our mostly Caucasian families. However, a role cannot be excluded in other populations such as the Japanese, among whom linkage to diabetes is also observed at 8p23 and a non-synonymous mutation has been detected in the PPP1R3B gene.
PPP1R3B基因（G(L)）的产物是PP1的调节亚基，PP1是一种丝氨酸/苏氨酸磷酸酶，参与肝脏和骨骼肌中糖原合成的调节。PPP1R3B基因位于8号染色体p23区域，该区域与2型糖尿病和青少年成年发病型糖尿病（MODY）有关。我们研究了PPP1R3B基因座处的序列变异是否是导致该位置观察到的与糖尿病连锁的原因。逆转录-聚合酶链反应（RT-PCR）分析揭示了两个可变启动子的存在。在13个乔斯林家族的先证者中对该基因的这些以及两个外显子进行了测序，这些家族在8p23处显示出最强的连锁证据。共观察到20个变异：两个在5'侧翼区域，一个在内含子（外显子2的5'端9 bp处），17个在3'非翻译区（UTR）。内含子变异产生了一个新的受体剪接位点，导致产生了一个具有更长5'UTR的可变剪接变体。然而，在这13个“连锁”家族中，无论是这个变异还是其他变异都没有与糖尿病共分离。此外，乔斯林研究中的90个家族先证者和347个无关对照的等位基因频率相似。因此，在我们主要为白种人的家族中，PPP1R3B基因的遗传变异似乎对糖尿病没有影响。然而，在其他人群中不能排除其作用，比如日本人，在他们当中也观察到8p23与糖尿病的连锁，并且在PPP1R3B基因中检测到了一个非同义突变。
