Freeman Natasha S, Bogyo Kelsie, Beenken Andrew, Nestor Jordan G, Sanna-Cherchi Simone, Canetta Pietro A
Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Glomerular Dis. 2025 May 2;5(1):243-249. doi: 10.1159/000546242. eCollection 2025 Jan-Dec.
MYH9-related disease (MYH9-RD) is a rare genetic cause of proteinuric kidney disease. It typically manifests as a syndromic condition, presenting with macrocytic thrombocytopenia, sensorineural hearing loss (SNHL), chronic glomerulopathy, elevated liver enzymes, and early-onset bilateral cataracts. In accordance with CARE guidelines, we present a case report of a father and daughter with renal-predominant MYH9-RD due to a recently described missense variant affecting the head domain of non-muscle myosin heavy chain IIA.
Patient 1 was an 18-year-old woman with childhood proteinuria who presented with severely advanced kidney failure. Dialysis was initiated as a bridge to a living unrelated renal transplant (LURT). Family history was notable for proteinuric kidney disease in her father (patient 2). Eight years later, genetic testing identified a likely pathogenic missense variant in the head domain of the gene (c.1271G>A, p.R424Q). A predictive structural model was obtained via AlphaFold Protein Structure Database, in which the mutation interrupts hydrogen bonding and π-cation interactions, likely leading to protein misfolding. Subsequent clinical screening revealed persistent mild thrombocytopenia and elevated liver enzymes, without cataracts or SNHL. Patient 2 was a 53-year-old man with childhood proteinuria who eventually presented with stage 4 chronic kidney disease and soon after underwent LURT. After patient 1's genetic diagnosis, he was confirmed to have the same mutation by genetic testing. Subsequent screening revealed mild thrombocytopenia and elevated liver enzymes with hepatic steatosis progressing to cirrhosis, without cataracts or SNHL.
The finding of this p.R424Q variant confirmed a diagnosis of MYH9-RD in these patients. variants affecting the head domain typically result in severe thrombocytopenia. This recently reported head domain variant caused severe renal manifestations with mild thrombocytopenia and no manifestations of SNHL or cataracts in both patients, suggesting that this variant causes a renal-predominant form of MYH9-RD.
MYH9相关疾病（MYH9-RD）是蛋白尿性肾病的一种罕见遗传病因。它通常表现为一种综合征，伴有大细胞性血小板减少、感音神经性听力损失（SNHL）、慢性肾小球病、肝酶升高和早发性双侧白内障。根据CARE指南，我们报告一例父女患有以肾脏为主的MYH9-RD的病例，病因是最近发现的一个错义变异，影响非肌肉肌球蛋白重链IIA的头部结构域。
患者1是一名18岁女性，童年时出现蛋白尿，就诊时已处于严重晚期肾衰竭。开始透析作为过渡到非亲属活体肾移植（LURT）的桥梁。家族史显示其父亲（患者2）患有蛋白尿性肾病。八年后，基因检测在该基因的头部结构域发现一个可能致病的错义变异（c.1271G>A，p.R424Q）。通过AlphaFold蛋白质结构数据库获得了一个预测性结构模型，其中该突变中断了氢键和π-阳离子相互作用，可能导致蛋白质错误折叠。随后的临床筛查发现持续存在轻度血小板减少和肝酶升高，无白内障或SNHL。患者2是一名53岁男性，童年时出现蛋白尿，最终发展为4期慢性肾病，不久后接受了LURT。在患者1进行基因诊断后，他经基因检测证实有相同突变。随后的筛查发现轻度血小板减少和肝酶升高，肝脂肪变性进展为肝硬化，无白内障或SNHL。
该p.R424Q变异的发现确诊了这些患者的MYH9-RD。影响头部结构域的变异通常会导致严重血小板减少。这个最近报道的头部结构域变异导致了严重的肾脏表现，同时伴有轻度血小板减少，且两名患者均无SNHL或白内障表现，提示该变异导致了以肾脏为主型的MYH9-RD。
