Paris Descartes University, INSERM U781 and Ref Center of Metabolic Diseases, Necker Hospital, Paris, France.
Hum Mutat. 2010 Jul;31(7):E1564-73. doi: 10.1002/humu.21282.
Autosomal recessive LPIN1 mutations have been recently described as a novel cause of rhabdomyolysis in a few families. The purpose of the study was to evaluate the prevalence of LPIN1 mutations in patients exhibiting severe episodes of rhabdomyolysis in infancy. After exclusion of primary fatty acid oxidation disorders, LPIN1 coding sequence was determined in genomic DNA and cDNA. Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion. In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months. Secondary defect of mitochondrial fatty oxidation or respiratory chain was found in skeletal muscle of two patients. The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement Delta pah1 yeast for growth on glycerol, in contrast to normal LPIN1. Since more than 50% of our series harboured LPIN1 mutations, LPIN1 should be regarded as a major cause of severe myoglobinuria in early childhood. The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy.
最近，常染色体隐性 LPIN1 突变被描述为少数家族横纹肌溶解症的一个新病因。本研究旨在评估在婴儿期发生严重横纹肌溶解症的患者中 LPIN1 突变的患病率。在排除原发性脂肪酸氧化障碍后，在基因组 DNA 和 cDNA 中确定 LPIN1 编码序列。在研究的 29 名患者中，有 17 名（59%）携带隐性无义或移码突变，或大片段基因内缺失。在这 17 名患者中，横纹肌溶解症发作的平均年龄为 21 个月。两名患者的骨骼肌中发现了线粒体脂肪酸氧化或呼吸链的继发性缺陷。在 17 名患者中的 8 名（47%）中鉴定出基因内缺失，c.2295-866_2410-30del，均为高加索人，发生在常见单倍型的背景下，提示存在一个奠基者效应。这种缺失的人类 LPIN1 形式无法补充 Delta pah1 酵母在甘油上的生长，而正常的 LPIN1 则可以。由于我们的系列研究中有超过 50%的患者携带 LPIN1 突变，因此 LPIN1 应被视为儿童早期严重肌红蛋白尿的主要原因。基因内 LPIN1 缺失的高频度应该为肌肉活检前的快速诊断提供一个有价值的标准。
