PDF(Pubmed)
Abstract：
Primary polyneuropathy in the context of Seip-Berardinelli type 1 seipinopathy, or congenital generalized lipodystrophy type 1 (CGL1) has not been previously reported. We report the case history of a 27 year old female CGL1 patient presenting with an unusual additional development of non-diabetic peripheral neuropathy and learning disabilities in early adolescence. Whole exome sequencing (WES) of the patient genome identified a novel variant, homozygous for a 52 bp intronic deletion in the AGPAT2 locus, coding for 1-acylglycerol-3-phosphate O-acyltransferase 2, which is uniquely associated with CGL1 seipinopathies, with no molecular evidence for dual diagnosis. Functional studies using RNA isolated from patient peripheral blood leucocytes showed abnormal RNA splicing resulting in the loss of 25 amino acids from the patient AGPAT2 protein coding sequence. Stability and transcription levels for the misspliced AGPAT2 mRNA in our patient nonetheless remained normal. Any AGPAT2 protein produced in our patient is therefore likely to be dysfunctional. However, formal linkage of this deletion to the neuropathy observed remains to be shown. The classical clinical presentation of a patient with AGPAT2-associated lipodystrophy shows normal cognition and no development of polyneuropathy. Cognitive disabilities and polyneuropathy are features associated exclusively with clinical CGL type 2 arising from seipin (BSCL2) gene mutations. This case study suggests that in some genetic contexts, AGPAT2 mutations can also produce phenotypes with primary polyneuropathy.
摘要：
在Seip-Berardinelli1型seipinopathy的背景下，原发性多发性神经病，或先天性全身性脂肪营养不良1型（CGL1）以前没有报道。我们报告了一名27岁女性CGL1患者的病史，该患者在青春期早期表现出非糖尿病性周围神经病变和学习障碍的异常发展。患者基因组的全外显子组测序（WES）鉴定出一种新的变异体，AGPAT2基因座中52bp内含子缺失纯合，编码1-酰基甘油-3-磷酸O-酰基转移酶2，该酶与CGL1SEipinopathies独特相关，没有双重诊断的分子证据.使用从患者外周血白细胞中分离的RNA进行的功能研究显示异常的RNA剪接，导致患者AGPAT2蛋白编码序列丢失25个氨基酸。我们患者中错误剪接的AGPAT2mRNA的稳定性和转录水平仍然正常。因此，在我们的患者中产生的任何AGPAT2蛋白都可能是功能失调的。然而,这种缺失与观察到的神经病变的正式联系仍有待证明。患有AGPAT2相关脂肪营养不良的患者的经典临床表现显示正常的认知并且没有发展为多发性神经病。认知障碍和多发性神经病是仅与由seipin（BSCL2）基因突变引起的临床CGL2型相关的特征。这个案例研究表明，在某些遗传背景下，AGPAT2突变也可产生原发性多发性神经病的表型。
