一个伴α地中海贫血X连锁智力低下综合征家系的基因突变研究

Mutation analysis for a Chinese family featuring X-linked alpha thalassemia/mental retardation syndrome

目的对1个x连锁智力低下伴d地中海贫血综合征（alphathalassaemia／mentalretardationsyndrome，X-linked，ATR-X）的家系进行致病基因突变研究。方法根据患者的临床表型和家系的遗传特点，应用x染色体短串联重复序列位点的连锁分析，定位智力低下的基因位点，初步锁定目的基因后，应用聚合酶链反应技术扩增致病基因外显子及剪切位点，应用DNA序列测定技术分析患者及其父母的致病性突变。地中海贫血基因检测确定患者基因型。结果连锁分析提示ATRX基因可能是家系智力低下的致病基因。全部3例患者ATRX基因第9外显子均存在C．736C〉T（P．R246C）突变。3例患者的母亲及祖母均为该突变携带者。其余8名家系成员均未检测到该基因突变。a地中海贫血检测证实先证者及另1例患者均携带a珠蛋白基因的缺失，基因型分别为结论该家系ATRX基因的错义突变e．736CT位于该基因突变热点区域，P．R246C可能影响ATRX蛋白锌指蛋白结构域的功能，可能是该家系ATR-X综合征的发病原因。

Objective To identify potential mutation in a Chinese family featuring X-linked alpha thalassemia/mental retardation syndrome （ATR-X）. Methods Based on clinical symptoms and inheritance pattern, linkage analysis of X chromosome short tandem repeats （X-STR） loci was carried out to locate the candidate gene. Subsequently, sequences of exons and exon-intron boundaries of the candidate gene were amplified with polymerase chain reaction （PCR）. Potential mutations were detected by direct DNA sequencing. All patients were also analyzed for the trait of thalassemia. Results Linkage analysis indicated the candidate gene to be ATRX. Subsequently, a homozygous missense mutation c. 736CT （p. R246C） was found in exon 9 of ATRX in all of the 3 patients. And a heterozygous mutation c. 736CT （p. R246C） was also identified in the patient＇s mother and grandmother. Similar mutations were not detected in other members of the family. Alpha thalassemia was detected in the proband and another patient, whose genotypes were determined as respectively. Conclusion Missense mutation of c. 736CT in ATRX gene is a mutation hotspot, and p. R246C may disturb the function of ATRX-DNMT3- DNMT3L domain （ADD）, which may be responsible for the disease in this family.