PDF(Pubmed)
Abstract：
BACKGROUND: Genetic factors contribute to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Advances in genetic testing have enabled the identification of hereditary kidney diseases, including those caused by LMX1B mutations. LMX1B mutations can lead to nail-patella syndrome (NPS) or nail-patella-like renal disease (NPLRD) with only renal manifestations.
METHODS: The proband was a 13-year-old female who was diagnosed with nephrotic syndrome at the age of 6. Then she began intermittent hormone and drug therapy. When she was 13 years old, she was admitted to our hospital due to sudden chest tightness, which progressed to end-stage kidney disease (ESRD), requiring kidney replacement therapy. Whole-Exome Sequencing (WES) results suggest the presence of LMX1B gene mutation, c.737G > T, p.Arg246Leu. Tracing her family history, we found that her father, grandmother, uncle and 2 cousins all had hematuria, or proteinuria. In addition to the grandmother, a total of 9 members of the family performed WES. The members with kidney involved all carry the mutated gene. Healthy members did not have the mutated gene. It is characterized by co-segregation of genotype and phenotype. We followed the family for 9 year, the father developed ESRD at the age of 50 and started hemodialysis treatment. The rest patients had normal renal function. No extra-renal manifestations associated with NPS were found in any member of the family.
CONCLUSIONS: This study has successfully identified missense mutation, c.737G > T (p.Arg246Leu) in the homeodomain, which appears to be responsible for isolated nephropathy in the studied family. The arginine to leucine change at codon 246 likely disrupts the DNA-binding homeodomain of LMX1B. Previous research has documented 2 types of mutations at codon R246, namely R246Q and R246P, which are known to cause NPLRD. The newly discovered mutation, R246L, is likely to be another novel mutation associated with NPLRD, thus expanding the range of mutations at the crucial renal-critical codon 246 that contribute to the development of NPLRD. Furthermore, our findings suggest that any missense mutation occurring at the 246th amino acid position within the homeodomain of the LMX1B gene has the potential to lead to NPLRD.
METHODS: The proband was a 13-year-old female who was diagnosed with nephrotic syndrome at the age of 6. Then she began intermittent hormone and drug therapy. When she was 13 years old, she was admitted to our hospital due to sudden chest tightness, which progressed to end-stage kidney disease (ESRD), requiring kidney replacement therapy. Whole-Exome Sequencing (WES) results suggest the presence of LMX1B gene mutation, c.737G > T, p.Arg246Leu. Tracing her family history, we found that her father, grandmother, uncle and 2 cousins all had hematuria, or proteinuria. In addition to the grandmother, a total of 9 members of the family performed WES. The members with kidney involved all carry the mutated gene. Healthy members did not have the mutated gene. It is characterized by co-segregation of genotype and phenotype. We followed the family for 9 year, the father developed ESRD at the age of 50 and started hemodialysis treatment. The rest patients had normal renal function. No extra-renal manifestations associated with NPS were found in any member of the family.
CONCLUSIONS: This study has successfully identified missense mutation, c.737G > T (p.Arg246Leu) in the homeodomain, which appears to be responsible for isolated nephropathy in the studied family. The arginine to leucine change at codon 246 likely disrupts the DNA-binding homeodomain of LMX1B. Previous research has documented 2 types of mutations at codon R246, namely R246Q and R246P, which are known to cause NPLRD. The newly discovered mutation, R246L, is likely to be another novel mutation associated with NPLRD, thus expanding the range of mutations at the crucial renal-critical codon 246 that contribute to the development of NPLRD. Furthermore, our findings suggest that any missense mutation occurring at the 246th amino acid position within the homeodomain of the LMX1B gene has the potential to lead to NPLRD.
摘要：
背景：遗传因素有助于慢性肾病（CKD）和终末期肾病（ESRD）。基因检测的进展使遗传性肾脏疾病的识别成为可能，包括由LMX1B突变引起的。LMX1B突变可导致指甲髌骨综合征（NPS）或指甲髌骨样肾病（NPLRD），仅有肾脏表现。
方法：先证者是一名13岁女性，6岁时被诊断为肾病综合征。然后她开始间歇性激素和药物治疗。当她13岁的时候，她因突然胸闷入院,进展为终末期肾病（ESRD），需要肾脏替代疗法.全外显子组测序（WES）结果表明存在LMX1B基因突变，c.737G>T，p.Arg246Leu.追踪她的家族史,我们发现她的父亲,祖母,叔叔和两个表亲都有血尿,或蛋白尿。除了祖母，共有9名家庭成员进行了WES。涉及肾脏的成员都携带突变基因。健康成员没有突变基因。其特征在于基因型和表型的共分离。我们跟踪了这个家庭9年，父亲在50岁时发展为ESRD并开始血液透析治疗.其余患者肾功能正常。在该家族的任何成员中均未发现与NPS相关的肾外表现。
结论：本研究成功鉴定了错义突变，c.737G>T（p。Arg246Leu)在同源域中，这似乎是所研究家庭中孤立性肾病的原因。密码子246处的精氨酸到亮氨酸的改变可能破坏LMX1B的DNA结合同源结构域。先前的研究已经记录了密码子R246的2种类型的突变，即R246Q和R246P，已知会导致NPLRD。新发现的突变,R246L,可能是另一种与NPLRD相关的新突变，从而扩大了导致NPLRD发展的关键肾关键密码子246的突变范围.此外，我们的研究结果表明,任何发生在LMX1B基因同源结构域第246位氨基酸位置的错义突变都有可能导致NPLRD.
方法：先证者是一名13岁女性，6岁时被诊断为肾病综合征。然后她开始间歇性激素和药物治疗。当她13岁的时候，她因突然胸闷入院,进展为终末期肾病（ESRD），需要肾脏替代疗法.全外显子组测序（WES）结果表明存在LMX1B基因突变，c.737G>T，p.Arg246Leu.追踪她的家族史,我们发现她的父亲,祖母,叔叔和两个表亲都有血尿,或蛋白尿。除了祖母，共有9名家庭成员进行了WES。涉及肾脏的成员都携带突变基因。健康成员没有突变基因。其特征在于基因型和表型的共分离。我们跟踪了这个家庭9年，父亲在50岁时发展为ESRD并开始血液透析治疗.其余患者肾功能正常。在该家族的任何成员中均未发现与NPS相关的肾外表现。
结论：本研究成功鉴定了错义突变，c.737G>T（p。Arg246Leu)在同源域中，这似乎是所研究家庭中孤立性肾病的原因。密码子246处的精氨酸到亮氨酸的改变可能破坏LMX1B的DNA结合同源结构域。先前的研究已经记录了密码子R246的2种类型的突变，即R246Q和R246P，已知会导致NPLRD。新发现的突变,R246L,可能是另一种与NPLRD相关的新突变，从而扩大了导致NPLRD发展的关键肾关键密码子246的突变范围.此外，我们的研究结果表明,任何发生在LMX1B基因同源结构域第246位氨基酸位置的错义突变都有可能导致NPLRD.
