Feather S A, Woolf A S, Donnai D, Malcolm S, Winter R M
Molecular Genetics Unit, Institute of Child Health, London, UK.
Hum Mol Genet. 1997 Jul;6(7):1163-7. doi: 10.1093/hmg/6.7.1163.
Key features of the oral-facial-digital syndrome type 1 (OFD1) include malformations of the face, oral cavity and digits. In addition, the clinical phenotype often includes mental retardation and renal functional impairment. Approximately 75% of cases of OFD1 are sporadic, and the condition occurs almost exclusively in females. In familial cases, the most likely mode of inheritance is considered to be X-linked dominant with prenatal lethality in affected males. Therefore, the OFD1 gene product appears to have widespread importance in organogenesis and is essential for fetal survival. We have studied two kindreds in which the clinical course was dominated by polycystic kidney disease requiring dialysis and transplantation. Using polymorphic chromosome markers spaced at approximately 10 cM intervals along the X chromosome, we mapped the disease to a region on the short arm of the X chromosome (Xp22.2-Xp22.3) spanning 19.8 cM and flanked by crossovers with the markers DXS996 and DX7S105. There was a maximum lod score of 3.32 in an 'affecteds only' analysis using a marker within the KAL gene (theta = 0.0 ), thereby confirming the location of the gene for OFD1 on the X chromosome. The remainder of the X chromosome was excluded by recombinants in affected individuals. The importance of our findings includes the definitive assignment of this male-lethal disease to the X chromosome and the mapping of a further locus for a human polycystic kidney disease. Furthermore, this mapping study suggests a possible mouse model for OFD1 as the X-linked dominant Xpl mutant, in which polydactyly and renal cystic disease occurs, maps to the homologous region of the mouse X chromosome.
1型口面指综合征（OFD1）的主要特征包括面部、口腔和手指的畸形。此外，临床表型通常还包括智力发育迟缓及肾功能损害。OFD1病例约75%为散发性，且该病症几乎仅发生于女性。在家族性病例中，最可能的遗传方式被认为是X连锁显性遗传，患病男性会出现产前致死。因此，OFD1基因产物似乎在器官发生过程中具有广泛的重要性，并且对胎儿存活至关重要。我们研究了两个家系，其临床病程以需要透析和移植的多囊肾病为主。利用沿X染色体以约10厘摩间隔分布的多态性染色体标记，我们将该疾病定位到X染色体短臂（Xp22.2 - Xp22.3）上一个跨度为19.8厘摩的区域，该区域两侧与标记DXS996和DX7S105发生了交换。在使用KAL基因内一个标记进行的“仅对患者”分析中，最大连锁值为3.32（θ = 0.0），从而证实了OFD1基因在X染色体上的位置。患病个体中的重组体排除了X染色体的其余部分。我们研究结果的重要性包括将这种男性致死性疾病明确定位于X染色体，并确定了人类多囊肾病的另一个基因座。此外，这项定位研究表明，X连锁显性Xpl突变体可能是OFD1的小鼠模型，其中多趾和肾囊性疾病映射到小鼠X染色体的同源区域。
