Selective loss of a LAP1 isoform causes a muscle-specific nuclear envelopathy

TOR1AIP1-Associated Nuclear Envelopathies

“…The physiological roles of LAP1 in humans have not been entirely deciphered; however, evidence from animal models, studies of cultured human cells, and bioinformatic analyses have linked LAP1 to a large variety of cellular pathways and biological processes. Moreover, the clinical relevance of LAP1 in human physiology is supported by the absence of homozygous deletion, duplication, or nonsense mutations in TOR1AIP1 in the healthy population [ 5 ] and the association of mutations in TOR1AIP1 with tissue-specific pathological processes [ 3 , 4 , 5 , 6 , 7 , 8 , 10 , 12 ] (OMIM #614512). LAP1 has highly specific roles in restricted cell or tissue types and ubiquitous functions in DNA repair and mitosis as described in this section.…”

“…TOR1AIP1 mutations have been reported in patients with skeletal muscle disorders with or without cardiomyopathies. In muscle biopsies from several of these patients, central nuclei, myofiber degeneration, and/or ultrastructural alterations of the nuclear envelope were observed [ 4 , 5 , 6 , 7 , 9 , 11 , 12 ], suggesting that LAP1 is necessary for the integrity of myonuclei and normal muscular structure in humans.…”

“…Kayman-Kurekci et al were the first to report an LAP1-associated phenotype in humans; in 2014, these authors identified three affected patients from a Turkish family who each carried a frameshift mutation (c.186delG) in the TOR1AIP1 gene. To date, only 23 patients have been identified with mutations in TOR1AIP1 , and all pathogenic variants were inherited in a recessive manner [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Similarly to what has been described in other nuclear envelopathies, the clinical spectrum reported in the literature is broad, ranging from isolated tissue-specific disease to complex multisystemic disorders.…”

“…Although its exact biological functions remain incompletely understood, LAP1 has been linked to a large variety of both ubiquitous and tissue-specific cellular processes in animals and humans, as detailed in this review. Variants in TOR1AIP1 and their associate phenotypes have been described in several case reports and case series, with a total of 23 affected patients reported worldwide [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. The aims of this review are to summarize what is known regarding the functions of LAP1 in human health and disease, and to provide a comprehensive overview of TOR1AIP1 -related disorders.…”

Hepatocytes Deficient in Nuclear Envelope Protein Lamina-associated Polypeptide 1 are an Ideal Mammalian System to Study Intranuclear Lipid Droplets

“…Little is known about the functional differences between these isoforms; however, they are all expressed in most tissues with some differences depending upon the developmental stage ( 37 ). Humans apparently express only LAP1B and LAP1C ( 38 ) and genetic studies have shown that mutations leading to deletion of both cause multisystem disease with death during childhood ( 39 ) while recessive mutations that disrupt only LAP1B cause cardiomyopathy and muscular dystrophy ( 40 , 41 , 42 , 43 ).…”