无精子症是至少两次精液检查均未发现精子，约占男性不育的10-20%。但对人无精子症的分子基础和机制，仍了解甚少。我们用全外显子测序和生物信息学分析的方法在巴基斯坦近亲婚配家系的无精子症患者中发现剪接因子SF1特异转录本的纯合移码突变，并制备了相应突变小鼠，发现移码突变产生的敲除小鼠不育且精子发生异常。为阐明SF1突变如何导致人和小鼠精子发生异常，拟开展以下工作：首先，分析SF1敲除和突变敲入小鼠表型，确定突变影响的精子发生阶段；进而研究SF1突变对剪接的影响，鉴别SF1调控的靶基因；最后，用SF1突变携带者睾丸组织切片对SF1及靶基因的表达和定位进行分析。以期发现并证实SF1纯合移码突变导致人类无精子症，揭示突变致病机理，为相关无精子症患者基因诊断和人工辅助生殖胚胎遗传诊断提供分子标志。

Azoospermia, defined as no sperm in semen for at least two examinations, is reported in up to 10-20% of infertile men. The molecular basis and mechanism need to be elucidated. Previously, we found a homologous frameshift mutation of splicing factor SF1 gene in a specific transcript in azoospermia patients from a Pakistani consanguineous family and the some region mutation in mice results in male infertility and spermatogenic abnormalities. In this project, we will analyze the phenotype of SF1 knockout and knockin mice to find out which stage of spermatogenesis is affected, then we will study SF1’s role on mRNA splicing to identify SF1 regulated mRNAs, finally we will try to determine the expression and localization of SF1 and its target proteins in SF1 mutated testicular tissue. Our work will confirm that mutation in SF1 can cause azoospermia in human and reveal its pathogenic mechanism, providing molecular markers for genetic diagnosis of azoospermia patients and in early embryos derived from assisted reproductive technology.