General information: The SALSA MLPA Probemix P048-C3 LMNA/MYOT/ZMPSTE24 is a research use only (RUO) assay for the detection of deletions or duplications in the LMNA, MYOT, CAV3 and ZMPSTE24 genes, which is associated with Laminopathies.

Laminopathies have emerged as clinically heterogeneous genetic disorders due to mutations in lamins or lamin-associated proteins. Lamins are structural protein components of the nuclear lamina, a protein network underlying the inner nuclear membrane that determines nuclear shape and size. The lamins constitute a class of intermediate filaments. Three types of lamins, A, B, and C, have been described in mammalian cells.

Laminopathies regroup at least eight distinct diseases, belonging to the groups of skeletal and/or cardiac muscular dystrophies, axonal neuropathies, premature ageing syndromes and familial lipodystrophies. These diseases, such as Emery-Dreifuss muscular dystrophy, Hutchinson-Gilford progeria syndrome and limb-girdle muscular dystrophy type 1B (LGMD1B), result from alterations in the LMNA gene, encoding type A-lamins.

Pathophysiological mechanisms explaining how mutations in a unique gene could lead to such various phenotypes are still unknown, but probably involve alterations in cellular mechanical stress responses, in gene expression, and/or in post-translational maturation of lamin A. One gene that is involved in the post-translational processing of lamin A precursor is ZMPSTE24 (also known as FACE1 in human). Loss of function of the ZMPSTE24 gene and accumulation of precursor lamin A has been correlated with restrictive dermopathy (RD).

Mutations in the MYOT gene are associated with LGMD1A and myofibrillar myopathies. Mutations in the CAV3 gene are associated with LGMD1C.

The LMNA gene (12 exons), spans ~25.4 kb of genomic DNA and is located on 1q22, ~156 Mb from the p-telomere. The ZMPSTE24 gene (10 exons), spans ~36 kb of genomic DNA and is located on 1p34.2, ~40 Mb from the p-telomere. The MYOT gene (10 exons), spans ~20 kb of genomic DNA and is located on chromosome 5q31.2, ~138 Mb from the p-telomere. The CAV3 gene (2 exons), spans ~13 kb of genomic DNA and is located on chromosome 3p25.3, ~8.8 Mb from the p-telomere.

More information is available at https://www.ncbi.nlm.nih.gov/books/NBK304462/.

Probemix content: The SALSA MLPA Probemix P048-C3 LMNA/MYOT/ZMPSTE24 contains 44 MLPA probes with amplification products between 131 and 463 nucleotides (nt). The P048-C3 probemix contains probes for all 12 exons of the LMNA gene. Two probes are present for exon 1. This probemix furthermore contains probes for all exons of the ZMPSTE24, MYOT and CAV3 genes. In addition, nine reference probes are included that detect autosomal chromosomal locations. Complete probe sequences and the identity of the genes detected by the reference probes are available online (www.mlpa.com).

This probemix contains nine quality control fragments generating amplification products between 64 and 105 nt: four DNA Quantity fragments (Q-fragments), two DNA Denaturation fragments (D-fragments), one Benchmark fragment, and one chromosome X and one chromosome Y-specific fragment. More information on how to interpret observations on these control fragments can be found in the MLPA General Protocol and online at www.mlpa.com.