Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within the 1st decade of life. Here, we have identified compound heterozygosity in TOR1AIP1 affecting both LAP1 isoforms in two unrelated individuals affected by congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival. Cellular characterization of primary fibroblasts of one affected individual revealed absence of both LAP1B and LAP1C, constitutively low lamin A/C levels, aberrant nuclear morphology including nuclear cytoplasmic channels, and premature senescence, comparable to findings in other progeroid forms of nuclear envelopathies. We additionally observed an abnormal activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2). Ectopic expression of wild-type TOR1AIP1 mitigated these cellular phenotypes, providing further evidence for the causal role of identified genetic variants. Altogether, we thus further expand the TOR1AIP1-associated phenotype by identifying individuals with biallelic loss-of-function variants who survived beyond the 1st decade of life and reveal novel molecular consequences underlying the TOR1AIP1-associated disorders.

中文翻译：

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两个新的情况进一步扩大了与TOR1AIP1相关的核信封的表型。

TOR1AIP1中的双等位基因变异体编码具有两个功能同工型LAP1B和LAP1C的完整核膜蛋白LAP1（椎板相关多肽1），最初已与患有心脏和神经功能异常的肌营养不良有关。此外，在生命的第一个十年中，在受多系统异常影响的七个可能相关的个体中，鉴定出了导致两个LAP1亚型丢失的复发性纯合性无意义改变。在这里，我们已经确定了TOR1AIP1中的复合杂合性，影响到两个无关的个体，这两个个体均受先天性双侧听力损失，室间隔缺损，双侧白内障，轻度至中度发育迟缓，小头畸形，下颌发育不全，矮小，进行性肌萎缩症的影响，关节挛缩和严重的慢性心力衰竭，生存期更长。一名受影响个体的原代成纤维细胞的细胞特征显示，既没有LAP1B也没有LAP1C，lamin A / C水平低，包括核胞质通道在内的异常核形态，以及过早衰老，与其他早熟形式的核包膜病的发现相当。我们还观察到细胞外信号调节激酶1/2（ERK 1/2）的异常激活。野生型TOR1AIP1的异位表达减轻了这些细胞表型，为鉴定的遗传变异的因果作用提供了进一步的证据。共，