X-linked Alport syndrome: auditory pathogenic variant features and further genotype-phenotype correlations in female patients
-
摘要: 目的:分析国人X连锁Alport综合征女性患者的临床听力学特点,并探讨其听力表型与基因型之间的关系。方法:总结64例X连锁Alport综合征女性患者的临床资料,对主要临床听力学表现进行回顾性分析,并采用检测皮肤成纤维细胞mRNA的方法或外周血DNA扩增直接测序的方法对患者进行IV型胶原α5链基因的检测。按照突变类型分为轻型突变和重型突变,并进行临床表型和基因型关系分析。结果:64例女性患者均有血尿或蛋白尿,均行纯音测听、声导抗检查,其中听力正常者51例,听力下降者13例,均表现为轻度或中度双侧对称性感音神经性聋,均以中频听力下降为主,听力曲线为槽型。64例患者中52例检测出COL4A5基因突变,共检出42种突变。听力损失患者中,除1例12岁外,其余均 ≥ 35岁。25例 ≥ 35岁患者中,轻型突变13例(10例听力正常,3例听力轻度下降),重型突变12例(6例听力正常,6例听力轻中度下降)。随访 ≥ 2年者26例,其中7例听力呈下降趋势,均为随访2年者,每年下降约5 dB,余听力无明显变化。结论:国人X连锁Alport综合征女性患者,早年出现血尿或蛋白尿,多于中年后开始出现迟发进展性听力损失,多为轻中度,曲线为槽型;听力损失发生时间较男性患者晚,并且听力损失严重程度较男性轻;听力表型与基因型之间未发现明显相关性。
-
关键词:
- Alport综合征,女性 /
- 听力学特征 /
- 基因突变 /
- 聋
Abstract: Objective: To analyze the audiological characteristics of female patients with X-linked Alport syndrome and to explore the relationship between genotype and phenotype in China.Method: The hearing data of 64 females diagnosed as Alport syndrome was reviewed and analyzed. All coding exons of COL4A5 genes were PCR-amplified and sequenced with genomic DNA, or mRNA of COL4A5 gene was RT-PCR amplified and sequenced with skin fibroblast.Result: The 64 cases who were accompanied by hematuria or proteinuria all received pure tone audiometry and acoustic immitance test. The incidence of hearing loss was 20.31% (13/64). The hearing were bilaterally symmetrical sensorineural deafness, most of which were mild and moderate hearing loss. The hearing curve is the groove curve. Among the 64 patients, 42 kinds of DNA variants were detected in 52 cases. Among the patients with hearing loss, 1 of them was 12 years old and the rest were over 35 years old. Mild mutations in 13 cases (10 cases of normal hearing and 3 cases of mild hearing loss) and severe mutations in in 12 cases (6 cases of normal hearing and 6 cases of mild to moderate hearing loss) were found in 25 cases over 35 years old. A total of 26 cases were followed up for 2 years or more, of which 7 cases had a downward trend of hearing loss, decreased about 5 dB each year, and there was no significant change in the hearing of the other patients.Conclusion: Mild and moderate hearing impairment, and groove type of audiometric curve are mainly found in Chinese X-linked Alport syndrome in females. Hearing loss occurs at middle-age. The onset time of hearing loss was later than that of the male, and the severity of hearing loss was lighter than that of the male. In the course of follow-up, some patients had a downward trend in hearing, and there was no significant correlation between the hearing phenotype and the genotype.-
Key words:
- Alport syndrome, female /
- hearing features /
- gene mutation /
- deafness
-
[1] KASHTAN C E,MICHAEL A F.Alport syndrome[J].Kidney Int,1996,50:1445-1463.
[2] PIRSON Y.Making the diagnosis of Alport's syndrome[J].Kidney Int,1999,56:760-775.
[3] LEVY M,FEINGOLD J.Estimating prevalence in single-gene kidney diseases progressing to renal failure[J].Kidney Int,2000,58:925-943.
[4] ALVES F R,DE A QUINTANILHA RIBEIRO F.Revision about hearing loss in the Alport's syndrome,analyzing the clinical genetic and bio-molecular aspects[J].Braz J Otorhinolaryngol,2005,71:813-819.
[5] 陈丽,薛俊芳,张琰琴,等.Alport综合征的临床听力学特点分析[J].中华耳鼻咽喉头颈外科杂志,2014,49(11):902-907.
[6] FLINTER F A,CAMERON J S,CHANTLER C,et al.Genetics of classic Alport's syndrome[J].Lancet,1988,2:1005-1007.
[7] ALVES F R,RIBEIRO F A.Clinical data and hearing of individuals with Alport syndrome[J].Braz J Otorhinolaryngol,2008,74:807-814.
[8] 王芳,丁洁,俞礼霞,等.检测皮肤成纤维细胞cDNA确定Alport综合征COL4A5/4/3基因突变[J].北京大学学报(医学版),2002,34(3):219-224.
[9] ZHANG Y,WANG F,DING J,et al.Genotype-phenotype correlations in 17 Chinese patients with autosomal recessive Alport syndrome[J].Am J Med Genet A,2012,158A:2188-2193.
[10] JAIS J P,KNEBELMANN B,GIATRAS I,et al.X-linked Alport syndrome:natural history in 195 families and genotype-phenotype correlations in males[J].J Am Soc Nephrol,2000,11:649-657.
[11] 杨涛,张学武.Alport综合征基因学研究进展[J].中国中西医结合肾病杂志,2006,7(4):242-244.
[12] RHEAULT M N.Women and Alport syndrome[J].Pediatr Nephrol,2012,27:41-46.
[13] BARKER D F,PRUCHNO C J,JIANG X,et al.A mutation causing Alport syndrome with tardive hearing loss is common in the western United States[J].Am J Hum Genet,1996,58:1157-1165.
[14] FLINTER F.Alport's syndrome[J].J Med Genet,1997,34:326-330.
[15] PERSIKOV A V,PILLITTERI R J,AMIN P,et al.Stability related bias in residues replacing glycines within the collagen triple helix(Gly-Xaa-Yaa)in inherited connective tissue disorders[J].Hum Mutat,2004,24:330-337.
[16] HUDSON B G, TRYGGVASON K, SUNDARAMOORTHY M, et al.Alport's syndrome,Goodpasture's syndrome,and type Ⅳ collagen[J].N Engl J Med,2003,348:2543-2556.
[17] ZEHNDER A F,ADAMS J C,SANTI P A,et al.Distribution of type Ⅳ collagen in the cochlea in Alport syndrome[J].Arch Otolaryngol Head Neck Surg,2005,131:1007-1113.
[18] KRUEGELJ,RUBEL D,GROSS O.Alport syndrome——insights from basic and clinical research[J].Nat Rev Nephrol,2013,9:170-178.
[19] BEKHEIRNIA M R,REED B,GREGORY M C,et al.Genotype-phenotype correlation in X-linked Alport syndrome[J].J Am Soc Nephrol,2010,21:876-83.
[20] YAMAMURA T,NOZU K,FU X J,et al.Natural History and Genotype-Phenotype Correlation in Female X-Linked Alport Syndrome[J].Kidney Int Rep,2017,2:850-855.
[21] KATJA S,JULIA H,CARSTEN B,et al.COL4A5-associated X-linked Alport syndrome in a female patient with early inner ear deafness due to a mutation in MYH9[J].Nephrol Dial Transplant,2012,27:4236-4240.
[22] PARDO C,HOOSE S A,PONDUGULA S,et al.DNA methyltransferase probing of chromatin structure within populations and on single molecules[J].Methods Mol Biol,2009,523:41-65.
[23] NAITO I,KAWAI S,NOMURA S,et al.Relationship between COL4A5 gene mutation and distribution of type Ⅳ collagen in male X-linked Alport syndrome.Japanese Alport Network[J].Kidney Int,1996,50:304-311.
[24] 张宏文,王芳,丁洁.年龄和组织类型对X连锁Alport综合征女性患者X染色体失活方式的影响[J].中国循证儿科杂志,2011,6(6):401-405.
[25] HEINE-SUÑER D,TORRES-JUAN L,MORLÀ M,et al.Fragile-X syndrome and skewed X-chromosome inactivation within a family:A female member with complete inactivation of the functional X chromosome[J].Am J Med Genet A,2003,122A:108-114.
计量
- 文章访问数: 162
- PDF下载数: 75
- 施引文献: 0