Identification of mutations in UBIAD1 following exclusion of coding mutations in the chromosome 1p36 locus for Schnyder crystalline corneal dystrophy.
Identification of mutations in UBIAD1 following exclusion of coding mutations in the chromosome 1p36 locus for Schnyder crystalline corneal dystrophy.
复制标题
DOI：
--
复制
发表时间：
2007-09
期刊：
影响因子：
2.2
通讯作者：
V. Yellore;M. A. Khan;N. Bourla;S. Rayner;Michael C Chen;B. Sonmez;R. Momi;K. Sampat;M. Gorin;A. Aldave
中科院分区：
文献类型：
--
作者：
V. Yellore;M. A. Khan;N. Bourla;S. Rayner;Michael C Chen;B. Sonmez;R. Momi;K. Sampat;M. Gorin;A. Aldave
目的通过对Schnyder结晶状角膜营养不良（SCCD）家系中与SCCD相关的位置候选基因和UBIAD 1的筛选，明确SCCD的遗传基础。方法采用聚合酶链反应（PCR）扩增和自动测序技术，对来自2个SCCD家系的4名患者的16个位置候选基因的编码区进行突变筛查。此外，UBIAD 1的编码区位于染色体1p36上最初描述的SCCD候选区间之外，直接对来自三个SCCD家族的受影响和未受影响的个体进行测序。结果在16个位置候选基因中的10个中鉴定出18个新的和15个先前报道的序列变异。在筛选的任一家族中，只有两个序列变体与受影响的表型分离。两者都是新的单核苷酸多态性（SNPs）预测导致同义氨基酸取代在不同的预测基因。然而，这些SNP之一也在对照个体中被鉴定，并且预测另一个SNP不会改变剪接。UBIAD 1的筛查揭示了三个无关的先证者中的每一个都有不同的错义突变：p.Asn102Ser，p.Arg119Gly和p.Leu121Val。对先证者中p.Asn102Ser和p.Leu121Val突变的受影响和未受影响的亲属进行筛选，结果表明每种突变与受影响的表型分离。在110个对照个体中没有发现这三种错义突变。结论在定位于SCCD候选区域的基因中未发现假定致病的编码区突变。然而，位于最初描述的SCCD精细定位区域之外的UBIAD 1中的错义突变在三个SCCD家族中的每一个中都被鉴定出，证实了UBIAD 1中的突变与SCCD相关。
PURPOSE To identify the genetic basis of Schnyder crystalline corneal dystrophy (SCCD) through screening positional candidate genes and UBIAD1, in which mutations have been associated with SCCD, in affected families. METHODS The coding region of each of the 16 positional candidate genes for which mutation screening has not been previously reported was screened with polymerase chain reaction (PCR) amplification and automated sequencing in four affected individuals from two families with SCCD. In addition, the coding region of UBIAD1, located just outside of the originally described SCCD candidate interval on chromosome 1p36, was directly sequenced in affected and unaffected individuals from three families with SCCD. RESULTS Eighteen novel and 15 previously reported sequence variants were identified in 10 of the 16 positional candidate genes. Only two of the sequence variants segregated with the affected phenotype in either of the families screened. Both were novel single nucleotide polymorphisms (SNPs) predicted to result in synonymous amino acid substitutions in different predicted genes. However, one of these SNPs was also identified in control individuals, and the other SNP was not predicted to alter splicing. Screening of UBIAD1 revealed a different missense mutation in each of the three unrelated probands that was screened: p.Asn102Ser, p.Arg119Gly, and p.Leu121Val. Screening of the affected and unaffected relatives of the probands in whom the p.Asn102Ser and p.Leu121Val mutations were identified demonstrated that each mutation segregated with the affected phenotype. None of the three missense mutations was identified in 110 control individuals. CONCLUSIONS No presumed pathogenic coding region mutations were identified in the genes mapped to the candidate region for SCCD. However, missense mutations in UBIAD1, located just outside of the originally described SCCD fine mapped region, were identified in each of the three families with SCCD, confirming that mutations in UBIAD1 are associated with SCCD.