Mutation Analysis of FOXF2 in Patients with Disorders of Sex Development (DSD) in Combination with Cleft Palate
Mutation Analysis of FOXF2 in Patients with Disorders of Sex Development (DSD) in Combination with Cleft Palate
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DOI：
10.1159/000195679
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发表时间：
2008-01-01
影响因子：
2.3
通讯作者：
Holterhus, P. M.
中科院分区：
文献类型：
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作者：
Jochumsen, U.;Werner, R.;Holterhus, P. M.
与缺乏雄激素产生或雄激素抑制作用引起的性别分化障碍相反，影响双能性生殖原发育的缺陷在人类中很少被研究。我们之前已经证实转录因子FOXF2在人类包皮中高度表达。此外，Foxf2基因敲除小鼠出现腭裂合并生殖器结节发育不全。我们假设患有性发育障碍（DSD）并腭裂的人可能有FOXF2基因突变。在Lubeck DSD数据库（约1,500个条目）中确定了18名患有DSD和腭裂的儿童。对FOXF2基因进行基因组DNA序列分析，并分别与10名正常女性和10名正常男性对照进行比较。两种杂合DNA序列变异仅在一名患者中存在，而在20名正常对照中均不存在：GCC （c.97GCC[9]+[10]）的重复导致外显子1内额外的丙氨酸和3'-非翻译区25*G > a的替换。2例患者携带c.262G > a序列变异，预测了Ala88Thr交换，在2例正常对照中也检测到。两个沉默突变，C . 1272c > T （Ser424Ser）和C . 1284t > C （Tyr428Tyr）分别发生在外显子2的编码区，同样发生在患者和正常对照中。总之，检测到的大部分序列改变是多态性，没有明显的功能相关性。然而，不能排除这2个独特的DNA序列改变可能在mRNA或蛋白质水平上影响FOXF2，从而导致生殖器和腭发育中观察到的紊乱。版权所有(c) 2009 S. Karger AG，巴塞尔
In contrast to disorders of sexual differentiation caused by lack of androgen production or inhibited androgen action, defects affecting development of the bipotent genital anlagen have rarely been investigated in humans. We have previously documented that the transcription factor FOXF2 is highly expressed in human foreskin. Moreover, Foxf2 knockout mice present with cleft palate in combination with hypoplasia of the genital tubercle. We hypothesized that humans with disorders of sex development (DSD) in combination with cleft palate could have mutations in the FOXF2 gene. Eighteen children with DSD and cleft palate were identified in the Lubeck DSD database (about 1,500 entries). Genomic DNA sequence analysis of the FOXF2 gene was performed and compared with 10 normal female and 10 normal male controls, respectively. Two heterozygous DNA sequence variations were solely present in one single patient each but in none of the 20 normal controls: a duplication of GCC (c.97GCC[9]+[10]) resulting in an extra alanine within exon 1 and a 25*G > A substitution in the 3'-untranslated region. Two patients carried a c.262G > A sequence variation predicting for an Ala88Thr exchange which was also detected in 2 normal controls. Two silent mutations, c.1272C > T (Ser424Ser) and c.1284T > C (Tyr428Tyr), respectively, occurred in the coding region of exon 2, again in both patients and normal controls. In conclusion, the majority of the detected sequence alterations were polymorphisms without obvious functional relevance. However, it cannot be excluded that the 2 unique DNA sequence alterations could have affected FOXF2 on the mRNA or protein level thus contributing to the observed disturbances in genital and palate development. Copyright (c) 2009 S. Karger AG, Basel