GENETIC STUDIES OF CRANIOFACIAL AND LIMB DISORDERS

Saethre-Chotzen综合征是一种最常见的常染色体显性遗传病 人类的颅突融合障碍，其特点是 头面部和四肢畸形。Saethre-Chotzen综合征的基因座 定位于染色体7p21-p22。我们已经评估了扭曲，一种基本的螺旋- 环螺旋转录因子，作为该病的候选基因 因为它在果蝇和果蝇中的表达模式和突变表型 小鼠符合Saethre-Chotzen表型。我们绘制了扭曲图 对人类染色体7p21-p22的突变分析 患者表现为无义、错义、插入和缺失突变 (Howard等人)1997年)。这些突变发生在基本DNA中 结合、螺旋I和环结构域，或导致过早终止 蛋白质的含量。 在Apert综合征中，以颅缝早闭和并指为特征 手和脚，丝氨酸-脯氨酸二肽的反复突变 (FGFR2 Ser252Trp或Pro253Arg) Ig III细胞外免疫球蛋白样结构域，已被证实 在160多个无关的个体中。我们进行了产前诊断 在检测到与此情况一致的特征的零星病例上 早在怀孕的前三个月(Filkins等人)1997年)。我们有 鉴定了该二肽的三个新的FGFR2突变，相关的 具有不同的颅缝融合症表型(Oldridge等人)。1997年)。一个CG 在一名男孩身上发现了预测Ser252Phe替换的T突变 轻度Crouzon综合征(四肢正常的颅缝早闭)也 出现在他的三个临床正常的家庭成员中。A CG-&gt；TT 预测Ser252Phe替换的突变导致表型 符合Apert综合征。最后，CGC-&GT；TCT突变 预测双氨基酸替代(Ser252Phe和Pro253Ser) 引起Pfeiffer综合征变异型，伴有轻度颅缝早闭 拇指和大脚趾，固定伸展几个指头，仅最小 皮肤并指症。 Treacher Collins综合征是人类最常见的 下颌面部骨质疏松症。最近，一个部分的TCOF1基因被克隆到 发现并证明在TCS家族中存在突变。在这里我们 给出完整的外显子/内含子基因组结构和完整的编码 TCOF1-TCOF1编码1411个氨基酸的低复杂性蛋白质 酸，其预测的蛋白质结构揭示了重复的基序 镜像其外显子的组织。这些主题与 核仁运输蛋白在其他物种中存在，预计 酪蛋白激酶高度磷酸化。与此一致的是，完全- 长度为TCOFI的蛋白质序列也含有可能的核和 核仁定位信号。在整个开放阅读框架中，我们 检测到另外八个突变和几个多态 对50多个TCS家庭进行了筛查(Wise等人)。1997年)。我们假设 TCS是由核仁运输蛋白的缺陷引起的 在人类颅面发育过程中是至关重要的。

Saethre-Chotzen syndrome is one of the most common autosomal dominant disorders of craniosynostosis in humans and is characterized by craniofacial and limb anomalies. The locus for Saethre-Chotzen syndrome maps to chromosome 7p21-p22. We have evaluated TWIST, a basic helix- loop-helix transcription factor, as a candidate gene for this condition because its expression pattern and mutant phenotypes in Drosophila and mouse are consistent with the Saethre-Chotzen phenotype. We mapped TWIST to human chromosome 7p21-p22, and mutational analysis on over 15 patients revealed nonsense, missense, insertion and deletion mutations (Howard et al. 1997). These mutations occur within the basic DNA binding, helix I and loop domains, or result in premature termination of the protein. In Apert syndrome, characterized by craniosynostosis and syndactyly of the hands and feet, recurrent mutations of the serine-proline dipeptide (either FGFR2 Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We performed prenatal diagnosis on a sporadic case with features consistent with this condition detected as early as the first trimester (Filkins et al. 1997). We have identified three novel FGFR2 mutations of this dipeptide, associated with distinct craniosynostotic phenotypes (Oldridge et al. 1997). A CG T mutation that predicts a Ser252Phe substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family. A CG->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome. Finally, a CGC->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. Treacher Collins syndrome is the most common of the human mandibulofacial dysostosis disorders. Recently, a partial TCOFl cDNA was identified and shown to contain mutations in TCS families. Here we present the entire exon/intron genomic structure and the complete coding sequence of TCOFl - TCOFl encodes a low complexity protein of 1411 amino acids, whose predicted protein structure reveals repeated motifs that mirror the organization of its exons. These motifs are shared with nucleolar trafficking proteins in other species and are predicted to be highly phosphorylated by casein kinase. Consistent with this, the full- length TCOFI protein sequence also contains putative nuclear and nucleolar localization signals. Throughout the open reading frame, we detected an additional eight mutations and several polymorphisms when over 50 TCS families were screened (Wise et al. 1997). We postulated that TCS results from defects in a nucleolar trafficking protein that is critically required during human craniofacial development.