Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9.
Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9.
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DOI：
10.1002/mgg3.165
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发表时间：
2015-11
影响因子：
2
通讯作者：
Fukami M
中科院分区：
文献类型：
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作者：
Katoh-Fukui Y;Igarashi M;Nagasaki K;Horikawa R;Nagai T;Tsuchiya T;Suzuki E;Miyado M;Hata K;Nakabayashi K;Hayashi K;Matsubara Y;Baba T;Morohashi K;Igarashi A;Ogata T;Takada S;Fukami M
SOX9单倍不全是伴或不伴睾丸发育不良的染色体异常增生（CD）的基础。目前对SOX9异常的表型变异性和突变谱的了解仍然不完整。在这里，我们报告了三例迄今未报道的SOX9异常患者。这些患者是通过对33例46，xy性发育障碍（DSD）患者的分子分析确定的。患者1 - 3表现为睾丸发育不良或退化，无CD。患者1和2分别在SOX9 C末端区域携带可能的破坏性突变p.a g394gly和p.a g437cys，但在其他已知的46xy DSD致病基因中没有。外显子组数据库中约12万个等位基因中没有这些替换。这些突变保留了Col2a1增强子的正常反激活活性，但Amh启动子的活性受损。患者3携带一个母体遗传的~ 491kb的SOX9上游缺失，包括已知的32.5 kb的XY性别逆转区。缺失的断点位于非重复序列中，并伴有短核苷酸插入。结果提示无骨骼发育不良的睾丸发育不良和退化可能是SOX9异常的罕见表现。此外，我们的数据扩大了致病性SOX9异常，包括导致靶基因特异性蛋白质功能障碍的C末端错义替换，以及由非同源末端连接介导的含有增强子的上游微缺失。
SOX9 haploinsufficiency underlies campomelic dysplasia (CD) with or without testicular dysgenesis. Current understanding of the phenotypic variability and mutation spectrum of SOX9 abnormalities remains fragmentary. Here, we report three patients with hitherto unreported SOX9 abnormalities. These patients were identified through molecular analysis of 33 patients with 46,XY disorders of sex development (DSD). Patients 1–3 manifested testicular dysgenesis or regression without CD. Patients 1 and 2 carried probable damaging mutations p.Arg394Gly and p.Arg437Cys, respectively, in the SOX9 C‐terminal domain but not in other known 46,XY DSD causative genes. These substitutions were absent from ~120,000 alleles in the exome database. These mutations retained normal transactivating activity for the Col2a1 enhancer, but showed impaired activity for the Amh promoter. Patient 3 harbored a maternally inherited ~491 kb SOX9 upstream deletion that encompassed the known 32.5 kb XY sex reversal region. Breakpoints of the deletion resided within nonrepeat sequences and were accompanied by a short‐nucleotide insertion. The results imply that testicular dysgenesis and regression without skeletal dysplasia may be rare manifestations of SOX9 abnormalities. Furthermore, our data broaden pathogenic SOX9 abnormalities to include C‐terminal missense substitutions which lead to target‐gene‐specific protein dysfunction, and enhancer‐containing upstream microdeletions mediated by nonhomologous end‐joining.