Mansilla M A, Cooper M E, Goldstein T, Castilla E E, Lopez Camelo J S, Marazita M L, Murray J C
Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA.
Cleft Palate Craniofac J. 2006 Jan;43(1):21-9. doi: 10.1597/04-169r.1.
Mutations in patched (PTCH) cause the nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome. Nevoid basal cell carcinoma syndrome may present with developmental anomalies, including rib and craniofacial abnormalities, and predisposes to several tumor types, including basal cell carcinoma and medulloblastoma. Cleft palate is found in 4% of individuals with nevoid basal cell carcinoma syndrome. Because there might be specific sequence alterations in PTCH that limit expression to orofacial clefting, a genetic study of PTCH was undertaken in cases with cleft lip and/or palate (CL/P) known not to have nevoid basal cell carcinoma syndrome.
Seven new normal variants spread along the entire gene and three missense mutations were found among cases with cleft lip and/or palate. One of these variants (P295S) was not found in any of 1188 control samples. A second variant was found in a case and also in 1 of 1119 controls. The third missense (S827G) was found in 5 of 1369 cases and in 5 of 1104 controls and is likely a rare normal variant. Linkage and linkage desequilibrium also was assessed using normal variants in and adjacent to the PTCH gene in 220 families (1776 individuals), each with two or more individuals with isolated clefting. Although no statistically significant evidence of linkage (multipoint HLOD peak = 2.36) was uncovered, there was borderline evidence of significant transmission distortion for one haplotype of two single nucleotide polymorphisms located within the PTCH gene (p = .08).
Missense mutations in PTCH may be rare causes of isolated cleft lip and/or palate. An as yet unidentified variant near PTCH may act as a modifier of cleft lip and/or palate.
patched（PTCH）基因的突变会导致痣样基底细胞癌综合征（NBCCS），即戈林综合征。痣样基底细胞癌综合征可能伴有发育异常，包括肋骨和颅面异常，并易患多种肿瘤类型，如基底细胞癌和髓母细胞瘤。4%的痣样基底细胞癌综合征患者存在腭裂。由于PTCH基因可能存在特定的序列改变，导致其表达局限于口腔颌面部裂隙，因此对已知不患有痣样基底细胞癌综合征的唇裂和/或腭裂（CL/P）病例进行了PTCH基因的遗传学研究。
在唇裂和/或腭裂病例中发现了7个沿整个基因分布的新的正常变异以及3个错义突变。其中一个变异（P295S）在1188个对照样本中均未发现。在一个病例以及1119个对照中的1个中发现了第二个变异。第三个错义突变（S827G）在1369个病例中的5个以及1104个对照中的5个中被发现，可能是一种罕见的正常变异。还使用PTCH基因及其邻近区域的正常变异对220个家庭（1776名个体）进行了连锁和连锁不平衡评估，每个家庭中有两个或更多个体患有孤立性裂隙。尽管未发现具有统计学意义的连锁证据（多点HLOD峰值 = 2.36），但对于位于PTCH基因内的两个单核苷酸多态性的一个单倍型，有临界证据表明存在显著的传递失真（p = 0.08）。
PTCH基因中的错义突变可能是孤立性唇裂和/或腭裂的罕见病因。PTCH基因附近尚未鉴定出的一个变异可能是唇裂和/或腭裂的修饰基因。
