Meyer J, Südbeck P, Held M, Wagner T, Schmitz M L, Bricarelli F D, Eggermont E, Friedrich U, Haas O A, Kobelt A, Leroy J G, Van Maldergem L, Michel E, Mitulla B, Pfeiffer R A, Schinzel A, Schmidt H, Scherer G
Institute of Human Genetics, University of Freiburg, Germany.
Hum Mol Genet. 1997 Jan;6(1):91-8. doi: 10.1093/hmg/6.1.91.
It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.
先前的研究表明，在杂合状态下，SOX9基因的突变会导致弯肢侏儒症（CD）以及常与之相关的常染色体XY性反转。在12例CD患者中，每个SOX9等位基因分别鉴定出10个新突变和1个复发突变，还有1例未发现突变。4个错义突变均位于高迁移率族（HMG）结构域内。它们要么降低要么消除了突变型SOX9蛋白的DNA结合能力。在鉴定出的5个无义突变和3个移码突变中，有2个使包含SOX9第402 - 509位残基的C末端反式激活（TA）结构域部分或几乎完全保持完整。在细胞转染实验中进行测试时，在分别存活了4年和9年以上的两名患者中发现的复发无义突变Y440X表现出一些残余的反式激活能力。相比之下，在一名出生后不久死亡的患者中发现的一个在第507位密码子处使蛋白质延长70个残基的移码突变则未表现出反式激活。如蛋白质印迹法所示，这显然是由于突变型SOX9蛋白不稳定所致。有无XY性反转的患者中均发现了氨基酸替代和无义突变，这表明CD中的性反转具有可变的外显率。最后，在18例XY性腺发育不全（Swyer综合征）的女性患者中，没有一例在单链构象多态性（SSCP）分析中显示SOX9条带模式改变，这证明SOX9突变通常不会在无骨骼畸形的情况下导致XY性反转。
