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目的通过对有近亲婚配史的Alport综合征一家系Ⅳ型胶原α3和α4链的COL4A3/COL4A4基因分析,明确常染色体隐性遗传Alport综合征的基因突变,为该病的基因诊断和家系遗传咨询提供更为全面的理论基础。方法PCR扩增先证者DNA COL4A3/COL4A4基因的共98个外显子,经直接测序,寻找突变位点,对有意义的突变经限制性内切酶AvaⅡ酶切在家系中分析验证。结果在该患者中共发现1个错义突变和10个序列变异。其中在COL4A3基因上发现一个位于42号外显子上的错义突变G3725A,导致蛋白质Gly1242Asp的突变。错义突变在患者中是纯合子,携带者中是杂合子,其他正常家系成员及筛查100条正常人染色体。未发现该突变。10个序列变异为单核苷酸多态性改变。结论报道了一个国内较少见的常染色体隐性遗传Alport综合征家系,同时经基因突变筛查发现Ⅳ型胶原α3链的一个新的致病性的基因突变。
OBJECTIVE: To determine the genetic mutation of Alport syndrome in autosomal recessive Alport syndrome by analyzing the COL4A3 / COL4A4 gene of α3 and α4 chains of Alport syndrome with a family history of inbreeding, so as to provide gene diagnosis and pedigree genetic counseling Provide a more comprehensive theoretical basis. Methods A total of 98 exons of DNA COL4A3 / COL4A4 gene were amplified by PCR. The sequences were directly sequenced and the mutation sites were searched. The meaningful mutations were analyzed by restriction endonuclease digestion with Ava Ⅱ in pedigrees. Results A total of one missense mutation and 10 sequence variations were found in this patient. Among them, a missense mutation G3725A was found on COL4A3 gene located on exon 42, resulting in the mutation of protein Gly1242Asp. Missense mutations are homozygous in patients, carriers are heterozygous, members of other normal families and screening for 100 normal human chromosomes. No mutation was found. Ten sequence variations were single nucleotide polymorphisms. Conclusion A rare autosomal recessive Alport syndrome pedigree was reported in China. A new virulence gene mutation was found in the α3 chain of type Ⅳ collagen by gene mutation screening.