Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1268, USA.
Semin Nephrol. 2010 Jul;30(4):409-17. doi: 10.1016/j.semnephrol.2010.06.007.
Genetic variation in MYH9, encoding nonmuscle myosin IIA heavy chain, has been associated recently with increased risk for kidney disease. Previously, MYH9 missense mutations have been shown to cause the autosomal-dominant MYH9 (ADM9) spectrum, characterized by large platelets, leukocyte Döhle bodies, and, variably, sensorineural deafness, cataracts, and glomerulopathy. Genetic testing is indicated for familial and sporadic cases that fit this spectrum. By contrast, the MYH9 kidney risk variant is characterized by multiple intronic single nucleotide polymorphisms, but the causative variant has not been identified. Disease associations include human immunodeficiency virus-associated collapsing glomerulopathy, focal segmental glomerulosclerosis, hypertension-attributed end-stage kidney disease, and diabetes-attributed end-stage kidney disease. One plausible hypothesis is that the MYH9 kidney risk variant confers a fragile podocyte phenotype. In the case of hypertension-attributed kidney disease, it remains unclear if the hypertension is a contributing cause or a consequence of glomerular injury. The MYH9 kidney risk variant is strikingly more common among individuals of African descent, but only some will develop clinical kidney disease in their lifetime. Thus, it is likely that additional genes and/or environmental factors interact with the MYH9 kidney risk variant to trigger glomerular injury. A preliminary genetic risk stratification scheme, using two single nucleotide polymorphisms, may estimate lifetime risk for kidney disease. Nevertheless, at present, no role has been established for genetic testing as part of personalized medicine, but testing should be considered in clinical studies of glomerular diseases among populations of African descent. Such studies will address critical questions pertaining to MYH9-associated kidney disease, including mechanism, course, and response to therapy.
MYH9 基因变异，编码非肌肉肌球蛋白 IIA 重链，最近与肾脏疾病风险增加相关。先前，MYH9 错义突变已被证实导致常染色体显性遗传 MYH9（ADM9）谱，其特征为巨大血小板、白细胞 Dǒhle 体，以及可变的感音神经性耳聋、白内障和肾小球病。具有这种谱的家族性和散发性病例需要进行基因检测。相比之下，MYH9 肾脏风险变异体的特征是多个内含子单核苷酸多态性，但尚未确定致病变异体。疾病关联包括人类免疫缺陷病毒相关性塌陷性肾小球病、局灶节段性肾小球硬化症、高血压归因的终末期肾病和糖尿病归因的终末期肾病。一个合理的假设是，MYH9 肾脏风险变异体赋予了脆弱的足细胞表型。在高血压归因的肾脏疾病中，仍不清楚高血压是肾小球损伤的促成因素还是后果。MYH9 肾脏风险变异体在非洲裔个体中更为常见，但只有一部分人在其一生中会发展为临床肾脏疾病。因此，很可能还有其他基因和/或环境因素与 MYH9 肾脏风险变异体相互作用，引发肾小球损伤。使用两个单核苷酸多态性的初步遗传风险分层方案可以估计终生患肾脏疾病的风险。然而，目前，基因检测尚未被确立为个性化医疗的一部分，但在非洲裔人群的肾小球疾病临床研究中应考虑进行检测。这些研究将解决与 MYH9 相关的肾脏疾病相关的关键问题，包括机制、病程和对治疗的反应。
