CAJ | 학술논문

目的：对2例低磷酸酶血症（ HPP）患者及家系进行分析和基因突变检测，拓展国人HPP致病基因库，探讨HPP的致病机制。方法对HPP家系先证者和其父母进行生化指标[血常规、肝肾功能、碱性磷酸酶（ ALP）、甲状旁腺素（ PTH）、钙、磷等]和骨密度检测。同时对所有研究对象进行alkaline phospatase ， live/bone/kidney （ ALPL）基因全部12个外显子和外显子内含子交界区直接测序。结果来自家系1的先证者为36岁成年男性，身高131.0 cm，体重35.0 kg。 X线提示多发性胸腰椎骨折和骨盆畸形，生化检测示血清ALP 27 U/L。测序发现ALPL基因6号外显子532位杂合突变（c.532T＞C），致ALPL成熟多肽中酪氨酸被组氨酸替代。该先证者母亲身高140.5 cm，体重39.5 kg，血清ALP 30 U/L，基因测序证明也是该杂合突变携带者。来自家系2的先证者5岁，其外祖父母为近亲结婚。该患儿身高100.0 cm，体重18 kg。血清ALP 55 U/L [低于同龄儿童正常范围（＜10岁）75～344 U/L]，牙齿发育不良并脱落，有左股骨中下端骨折史。测序发现该患儿存在ALPL基因2个错义突变，其中9号外显子c.871G＞A突变。4号外显子269位突变（c.269A＞G）是一个新的错义突变，该突变导致成熟ALPL多肽中天冬氨酸被甘氨酸所替代。该患儿母亲亦是4号外显子c.269A＞G错义突变携带者，但其生化指标正常，无骨骼和牙齿异常。结论 ALPL基因6号外显子c.532T＞C突变和4号外显子c.269A＞G突变是以往未曾报道过的新错义突变，为上述2例HPP患者致病基因。
목적：대2례저린산매혈증（ HPP）환자급가계진행분석화기인돌변검측，탁전국인HPP치병기인고，탐토HPP적치병궤제。방법대HPP가계선증자화기부모진행생화지표[혈상규、간신공능、감성린산매（ ALP）、갑상방선소（ PTH）、개、린등]화골밀도검측。동시대소유연구대상진행alkaline phospatase ， live/bone/kidney （ ALPL）기인전부12개외현자화외현자내함자교계구직접측서。결과래자가계1적선증자위36세성년남성，신고131.0 cm，체중35.0 kg。 X선제시다발성흉요추골절화골분기형，생화검측시혈청ALP 27 U/L。측서발현ALPL기인6호외현자532위잡합돌변（c.532T＞C），치ALPL성숙다태중락안산피조안산체대。해선증자모친신고140.5 cm，체중39.5 kg，혈청ALP 30 U/L，기인측서증명야시해잡합돌변휴대자。래자가계2적선증자5세，기외조부모위근친결혼。해환인신고100.0 cm，체중18 kg。혈청ALP 55 U/L [저우동령인동정상범위（＜10세）75～344 U/L]，아치발육불량병탈락，유좌고골중하단골절사。측서발현해환인존재ALPL기인2개착의돌변，기중9호외현자c.871G＞A돌변。4호외현자269위돌변（c.269A＞G）시일개신적착의돌변，해돌변도치성숙ALPL다태중천동안산피감안산소체대。해환인모친역시4호외현자c.269A＞G착의돌변휴대자，단기생화지표정상，무골격화아치이상。결론 ALPL기인6호외현자c.532T＞C돌변화4호외현자c.269A＞G돌변시이왕미증보도과적신착의돌변，위상술2례HPP환자치병기인。
Objective We aimed to analyze the clinical manifestations to identify the disease-causing mutations in Chinese hypophosphatasia patients , and to realize the racial difference between diversified ethnic groups .Methods In family 1, a 35 year-old nonconsanguineous male was the proband with the severe clinical manifestation of hypophos -phatasia, his mother displayed mild clinical symptoms .In family 2, the proband was a 5-year-old boy, and his consan-guineous parents had no abnormal sign .All 12 exons and the exon-intron boundaries of the ALPL gene were amplified and directly sequenced in two probands from two unrelated Chinese families .The mutation sites were validated in other unaf-fected members of these two families and 200 healthy controls.Results In family 1, one novel missense mutation c.532T>C which consisted of a heterozygous T >C transition at nucleotide 532 in exon 6 was detected in the proband and his mother.In family 2, the proband revealed two missense mutations in exon 4 and exon 9 respectively, the one in exon 4 was a novel mutation (c.269A>G) which resulted in p.Asp90Gly in the mature ALPL polypeptide.Another mutation was c.871G>A in exon 9, which had been already reported in 1998.His mother was a health carrier who harbored the same missense mutation in exon 4 without any clinical manifestations .Conclusion Our study showed that two novel mu-tations of the ALPL gene c.532T>C in exon 6 and c.269A>G in exon 4, taking responsibility for hypophosphatasia in Chinese patients .