Vanita Vanita, Hejtmancik James Fielding, Hennies Hans Christian, Guleria Kamlesh, Nürnberg Peter, Singh Daljit, Sperling Karl, Singh Jai Rup
Centre for Genetic Disorders, Guru Nanak Dev University, Amritsar, India.
Mol Vis. 2006 Feb 21;12:93-9.
The molecular characterization of 27 members of an Indian family, with 13 members in four generations, affected with Y-sutural congenital cataract.
Detailed family history and clinical data were collected. A genome-wide scan by two-point linkage analysis using more than 400 microsatellite markers in combination with multipoint lod score and haplotype analysis was performed. Mutation screening was carried out in the candidate gene by bi-directional sequencing of amplified products.
A maximum two-point lod score of 6.37 at theta=0.00 was obtained with marker D19S879. Haplotype analysis placed the cataract locus to a 5.0 cM region between D19S902 and D19S867, in close proximity to the L-ferritin light chain gene (FTL) on chromosome 19q13.3. Hematological tests in two affected individuals showed very high levels of serum ferritin without iron overload leading to the diagnosis of hyperferritinemia-cataract syndrome. Mutation screening in FTL identified a G>A change at position 32 (c.-168G>A) in a highly conserved 3 nucleotide motif that forms a loop structure in the iron responsive element (IRE) in the 5'-untranslated region (5'-UTR). This nucleotide alteration was neither seen in any unaffected member of the family nor found in 50 unrelated control subjects.
The present study is the first report of a Y-sutural congenital cataract mapping to 19q13.3. The mutation observed in FTL in this family highlights the phenotypic heterogeneity of the disorder in relation to the genotype as the identical mutation (32 G>A) has previously been reported in two Italian families with entirely different phenotypes. It is also the first report of hereditary hyperferritinemia-cataract syndrome in a family of Indian origin.
对一个印度家族的27名成员进行分子特征分析，该家族四代中有13名成员患有Y缝先天性白内障。
收集详细的家族史和临床数据。使用400多个微卫星标记通过两点连锁分析结合多点lod评分和单倍型分析进行全基因组扫描。通过对扩增产物进行双向测序在候选基因中进行突变筛查。
标记D19S879在θ=0.00时获得的最大两点lod评分为6.37。单倍型分析将白内障基因座定位到19号染色体19q13.3上D19S902和D19S867之间5.0 cM的区域，紧邻L-铁蛋白轻链基因（FTL）。两名受影响个体的血液学检查显示血清铁蛋白水平非常高，但无铁过载，从而诊断为高铁蛋白血症-白内障综合征。对FTL进行突变筛查，在5'-非翻译区（5'-UTR）铁反应元件（IRE）中形成环结构的高度保守的3核苷酸基序的第32位（c.-168G>A）发现了G>A变化。该核苷酸改变在该家族的任何未受影响成员中均未发现，在50名无关对照受试者中也未发现。
本研究是首次报道Y缝先天性白内障定位于19q13.3。该家族中在FTL中观察到的突变突出了该疾病在基因型方面的表型异质性，因为先前在两个具有完全不同表型的意大利家族中报道了相同的突变（32 G>A）。这也是印度裔家族中遗传性高铁蛋白血症-白内障综合征的首次报道。
