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一例抗維生素D佝僂病的基因診斷和新突變的致病性鑒定

·論著·

一例抗維生素D 佝僂病的基因診斷

和新突變的致病性鑒定

唐佳潘敬新蔣瑋瑩郭奕斌

DOI :10.3877/cma.j.issn.1674-0785.2012.05.083

基金項目:國家自然科學基金(30772069)

作者單位:510080廣州,中山大學中山醫學院醫學遺傳學教研室

(唐佳、蔣瑋瑩、郭奕斌);福建醫科大學第二附屬醫院內科(潘敬新)

通訊作者:郭奕斌,Email :guoyibin@mail.sysu.edu.cn 【摘要】目的

研究低血磷抗維生素D 佝僂病即X 連鎖低磷酸鹽血癥(XLH )患者發病的分子遺傳學機制,揭示其基因型與表現型的相互關系,為實施有效的對癥治療和今后的孕早期產前基因診斷創造必要的前提條件。方法在臨床初診的基礎上,采用PCR 及擴增產物直接測序法對先證者的PHEX 基因進行全面

的突變檢測;在檢出PHEX 基因c.2197-

2198insAACT 新突變后,采用PCR-DHPLC 篩檢法對隨機采集的108例正常對照的相應外顯子進行快速的突變篩查,以排除多態性變異的可能性,同時采用生物信息學方法對突變部位氨基酸的保守性和突變蛋白的二、三級結構進行預測分析,從而對其致病性進行鑒定。結果(1)先

證者PHEX 基因第22外顯子區域內存在一個新的雜合插入突變即c.2197-

2198insAACT 。(2)108例正常對照的DHPLC 篩檢和序列分析中,均未檢測到c.2197-2198insAACT 突變。(3)蛋白質二級、三級結構預測結

果顯示:c.2197-2198insAACT 新突變引起密碼子發生移位,導致肽鏈提前在第733位遇上終止密碼TAA ,致

使肽鏈從正常的749個氨基酸縮短至732個,

導致蛋白質二、三級結構發生明顯改變,而正常對照無此變化。結論PHEX 基因c.2197-2198insAACT 插入突變不是一般的多態性變異,而可能是一種新的致病性突變,它

極可能是引起先證者發病的根本內因?!娟P鍵詞】低磷血癥性佝僂病,X 連鎖顯性;

突變;毒力;PHEX 基因Genetic diagnosis for a patient with X-Linked hypophosphatemic rickets and identification of a novel pathologic mutation TANG Jia ,PAN Jing-xin ,JIANG Wei-ying ,GUO Yi-bin.Department of Medical Genetics ,SUN Yat-sen Medical School ,SUN Yat-sen University ,Guangzhou 510080,China

Corresponding author :GUO Yi-bin ,Email :guoyibin@mail.sysu.edu.cn

【Abstract 】Objective To study the molecular genetic mechanism of hypophosphatemic vitamin D resistant

rickets (X-linked hypophosphatemia ,XLH ),and reveal the relationship between the genotype and phenotype ,and provide a basis for effective symptomatic treatment and prenatal gene diagnosis in the future.Methods

Mutation detection was performed on the proband with PCR and direct sequencing of PCR products.After the novel mutation of

c.2197-2198insAACT in PHEX gene was detected ,

PCR-DHPLC was used to analysis 108randomly selected healthy controls in exon22of the PHEX gene ,in order to rule out the possibility of polymorphism ,at the same time ,bioinformatic approaches for protein secondary ,tertiary structure prediction were applied to identify the novel pathologic mutation.Results (1)One novel heterozygous insertion mutation (c.2197-2198insAACT )in exon22of PHEX gene was found in patient.(2)No ‘c.2197-2198insAACT ’mutation was found among 108cases of unaffected controls.(3)The results of protein secondary and tertiary structure prediction showed that the novel mutation (c.2197-2198insAACT )led to premature translational termination at amino acid position 733(p.C733X ),thus the peptide chain was shortened from 749to 732amino acids ,and secondary and tertiary protein structure change ,which were not found in all the controls.Conclusions The novel insertion mutation (c.2197-2198insAACT )in PHEX gene

probably is a novel pathologic mutation but not a polymorphism ,which may be responsible for the patient with XLH.【Key words 】Hypophosphatemic rickets ,X-linked dominant ;

Mutation ;Virulence ;PHEX genes 低血磷抗維生素D 佝僂病,又稱X 連鎖低磷酸鹽

血癥(X-linked hypophosphatemia ,XLH ;OMIM 307800),是一種常見的、X 連鎖顯性遺傳的佝僂?。?],發病率約為1?20000,女性患者較多[2]。本病臨床癥狀多樣,主要表現為身材矮小,骨骼疼痛,雙下肢彎曲畸形,骨軟化癥,骨質疏松,四肢無力,牙釉質發育不良[3]。磷酸鹽調節基因(phosphate regulating gene with homologies to ·6221·中華臨床醫師雜志(電子版)2012年3月第6卷第5期Chin J Clinicians (Electronic Edition ),March 1,2012,Vol.6,No.5

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