线粒体糖尿病家系基因突变的遗传学筛查

Molecular scanning of candidate mtDNA gene fragment in diabetic pedigrees

目的 探索与糖尿病发病相关的线粒体基因突变位点。方法 采用 PCR、DNA直接测序技术对 2 8个临床疑似线粒体基因突变糖尿病家系 ( mitochondrial diabetes mellitus,MDM)进行线粒体基因突变高发区域 ( t RNAL eu(UUR) 基因及 NADH脱氢酶 1基因 )的筛查。结果 两个家系发现与糖尿病发病有关的突变位点。其中 1个家系 ( 16号 )同时携带 nt32 4 3A→ G突变和 16 S r RNA32 0 5 C→ T突变。该家系两例患者均有消瘦、耳聋、β细胞功能低下、发病年龄低的特点 ,先证者血乳酸水平在正常高限。在另 1先证者患耳聋的家系 ( 2 8号 )发现 ND1基因 3434A→ G突变 ,导致氨基酸改变 ,与家系中糖尿病呈共同分离。上述突变均未在正常人中检测到。结论 32 4 3位点突变在本组家系中的发现率为 3.0 8%。 16 S r RNA32 0 5 C→ T突变可能与糖尿病发病有关或与 nt32 4 3A→ G突变协同作用。 ND1基因 3434A→ G突变与 2

Objective: To explore novel pathogenic mutation in the mitochondrial DNA gene in diabetic pedigree. Methods: Twenty-eight suspected mitochondrial DNA diabetic families were recruited. The gene fragment was produced by PCR, and mutation was detected by direct sequencing. Results: In one pedigree, the proband and her mother were found carrying the most common nt3243A&rarrG mutation and another 16S rRNA 3205C&rarrT mutation. But only 3205C&rarrT was found in her affected brother. All the two patients were deaf and developed diabetes in early age, characterized by impaired β cell function and low body mass index (BMI). The proband had relatively higher lactic acid concentration than normal individuals. A novel ND1 gene 3434 A&rarrG (TAT&rarrTGT) mutation was explored in another proband with deafness and her affected family members. Conclusion: 16SrRNA 3205C&rarrT mutation was found in a mitochondrial diabetes mellitus pedigree, implying its potential pathogenic role in diabetes. Another novel ND1 3434 A&rarrG mutation was found in another diabetic pedigree. Because this mutation causes amino acid change (Tyr&rarrCys) and is co-segregated with diabetes, it may be diabetogenic.