ITB-CNR, Segrate, MI Italy.
IRCCS Multimedica, Milan, Italy.
Immun Ageing. 2014 Nov 26;11(1):19. doi: 10.1186/s12979-014-0019-3. eCollection 2014.
LMNA/C mutations have been linked to the premature aging syndrome Hutchinson's progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease. One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this case, onset has been correlated with several mutations in genes essential for the proper maturation of cardiomyocytes, such as the gene for lamin A/C. However, no clear genotype-phenotype relationship has been reported to date between LMNA/C mutations and cardiomyopathies.
DNA and medical histories were collected from (n = 11) members of different generations of one family, the proband of which was implanted with a pacemaker for lone, type II AVB. Exome sequencing analysis was performed on three relatives with AVB, and the mutations therein identified validated in a further three AVB-affected family members. In the initial three AVB family members, we identified 10 shared nonsynonymous single-nucleotide variations with a rare or unreported allele frequency in the 1000 Genomes Project database. Follow-up genetic screening in the additional three affected relatives disclosed a correlation between the lone AVB phenotype and the single-nucleotide polymorphism rs56816490, which generates an E317K change in lamin A/C. Although this mutation has already been described by others in a DCM-affected proband with familiarity for AVB and sudden death, the absence of DCM in our large, AVB-affected family is indicative of genotype-phenotype correlation between rs56816490 and a familial, autosomal dominant form of lone AVB.
Screening for G613A in LMNA/C in patients with lone AVB and their relatives might prevent sudden death in families affected by AVB but without familiarity for DCM. Lone AVB is an age-related disease caused by mutations in LMNA/C gene rather than a complication of DCM.
LMNA/C 突变与早老综合征哈钦森-吉尔福德早衰症、扩张型心肌病 1A、骨骼肌病（如常染色体显性变异型肌营养不良症和肢带型肌营养不良症）、Charcot-Marie-Tooth 病 2B1 型、下颌面骨发育不良、常染色体显性部分脂肪营养不良症和轴索性神经病相关。房室传导阻滞 (AVB) 可与多种心脏疾病相关，它也可能是一种高度遗传性的原始疾病。与 AVB 相关的最常见病理之一是扩张型心肌病 (DCM)，其特征为心脏扩张和收缩功能降低。在这种情况下，发病已与几种对心肌细胞正常成熟至关重要的基因突变相关，例如核纤层蛋白 A/C 基因。然而，迄今为止，尚未报道 LMNA/C 突变与心肌病之间存在明确的基因型-表型关系。
收集了一个家系的不同世代的 11 名成员的 DNA 和医疗史，该家系的先证者因孤立性、II 型 AVB 植入了起搏器。对 3 名存在 AVB 的亲属进行外显子组测序分析，并在另外 3 名受 AVB 影响的家族成员中验证了其中的突变。在最初的 3 名 AVB 家族成员中，我们在 1000 基因组计划数据库中发现了 10 个罕见或未报告的等位基因频率的共享非同义单核苷酸变异。对另外 3 名受影响亲属的后续遗传筛查显示，孤立性 AVB 表型与单核苷酸多态性 rs56816490 相关，该突变导致核纤层蛋白 A/C 的 E317K 改变。尽管该突变已在另一名患有 AVB 和猝死家族史的 DCM 患者中被他人描述，但在我们这个大的、受 AVB 影响的家族中没有 DCM，表明 rs56816490 与常染色体显性孤立性 AVB 家族形式之间存在基因型-表型相关性。
在孤立性 AVB 患者及其亲属中筛查 LMNA/C 中的 G613A 可能会预防受 AVB 影响但无 DCM 家族史的患者发生猝死。孤立性 AVB 是一种由 LMNA/C 基因突变引起的与年龄相关的疾病，而不是 DCM 的并发症。
