Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure.

Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations.

Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death.

Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

背景对于许多肾衰竭患者，其病因和潜在缺陷仍然未知。在这里，我们描述了一种以肾脏Fanconi综合征和肾功能衰竭为特征的遗传顺序的新机制。

方法我们对5个常染色体显性遗传性肾范可尼综合征和肾功能衰竭家族的成员进行临床和遗传学特征分析。我们在肾活检标本和肾细胞中进行了全基因组连锁分析，测序和表达研究，以及敲除小鼠研究和线粒体形态和功能评估。结构研究检查了公认的突变的影响。

结果这些患者的肾脏疾病是由编码甘氨酸酰胺基转移酶（GATM）的基因中的单等位基因突变引起的，该基因是肌酸生物合成途径中的一种肾近端肾小管酶，否则与肌酸缺乏症的隐性疾病有关。计算机分析表明特定的GATM在五个家族的28个成员中鉴定出的突变，在GATM蛋白内产生了一个额外的相互作用界面，并可能导致在患者活检标本和培养的近端小管细胞中观察到的GATM线性聚集。含有GATM聚集体的线粒体被拉长并与ROS的产生增加，NLRP3炎性小体的激活，profibrotic细胞因子IL-18的表达增强以及细胞死亡增加有关。

结论在这种新的遗传疾病中，GATM中的完全渗透性杂合错义突变会触发GATM的线粒体内原纤维沉积，并导致线粒体延长和异常。我们推测，这种肾近端肾小管线粒体病理会引发炎症小体的反应，随后发生肾纤维化。