Abstract：
Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.
摘要：
已经报道了载脂蛋白A-IV髓样淀粉样变性的散发性病例。在这里，我们描述了由于两种不同的致病性APOA4变体而发现具有常染色体显性遗传性髓样淀粉样变性的五个家庭。一个具有常染色体显性遗传慢性肾脏疾病（CKD）和淡淡的尿沉渣的大家庭进行了全基因组测序，鉴定了chr11：116692578G>C（hg19）变体，该变体编码ApoA4蛋白的错义突变p.L66V。我们从我们的注册表中确定了另外两个具有相同变体的远亲家族和另外两个具有ch11：116693454C>T（hg19）变体编码错义突变p.D33N的远亲家族。这两种突变都是受影响家庭独有的，进化上保守并预测扩展ApoA4结构中的淀粉样蛋白生成热点。临床上受影响的人患有CKD，尿沉渣平淡，肾衰竭的平均年龄为64.5岁。基因分型鉴定了48个受遗传影响的个体;44个个体的估计肾小球滤过率(eGFR)低于60ml/min/1.73m2,包括所有25个患有肾衰竭的个体。重要的是,14个未受遗传影响的个体中的11个具有超过60ml/min/1.73m2的eGFR。15个受遗传影响的个体呈现较高的血浆ApoA4浓度。来自四个人的肾脏病理标本显示淀粉样沉积物仅限于髓质，在所有三个可用的活检中，通过质谱鉴定突变的ApoA4是主要的淀粉样蛋白成分。因此，ApoA4突变可引起常染色体显性遗传性髓样淀粉样变性，明显的淀粉样蛋白沉积仅限于肾髓质，并表现为常染色体显性遗传CKD，尿沉渣平淡。诊断依赖于仔细的家族史，APOA4测序和病理研究。
