The S573L homozygous LMNA mutation is associated with a novel phenotype of arthropathy, tendinous calcifications, and progeroid features distinct from the acroosteolysis previously reported in patients with mandibuloacral dysplasia caused by LMNA or ZMPSTE24 mutations.
Accordingly, mutations in the LMNA gene and functionally related genes have been described to cause HGPS (Hutchinson-Gilford progeria syndrome), MAD (mandibuloacral dysplasia) or RD (restrictive dermopathy).
Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse.
We conclude that MAD associated with ZMPSTE24 mutations has a more severe phenotype than that associated with LMNA mutations--probably reflecting the greater retention of unprocessed farnesylated prelamin A in the nucleus, which is toxic to cells.
Mandibuloacral dysplasia (MAD) is an autosomal recessive progeroid disorder associated with type A (partial) or B (generalized) lipodystrophy and is due to mutations in lamin A/C (LMNA) or zinc metalloproteinase (ZMPSTE24) genes.
Recently, mutations in lamin A/C (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post-translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds.
Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are well-recognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene.
Lamin A is a key component of the nuclear lamina produced through post-translational processing of its precursor known as prelamin A.LMNA mutations leading to farnesylated prelamin A accumulation are known to cause lipodystrophy, progeroid and developmental diseases, including Mandibuloacral dysplasia, a mild progeroid syndrome with partial lipodystrophy and altered bone turnover.
OCN is a major component of bone extracellular matrix and a marker of osteogenesis, whereas mutations in LMNA cause several genetic disorders called laminopathies, including mandibuloacral dysostosis (MAD) that manifests with low bone mass, severe bone deformities, and delayed closure of the cranial sutures.
Two genetic loci are known for MAD: lamin A/C (LMNA), encoding structural nuclear lamina proteins, and zinc metalloproteinase (ZMPSTE24), a membrane-bound endoprotease involved in post-translational proteolytic cleavage of carboxy terminal residues of prelamin A to form mature lamin A.
The associated mutant gene products include 1) nuclear lamin A in FPLD type 2 and MAD type A; 2) nuclear lamin B2 in APL; 3) nuclear hormone receptor peroxisome proliferator-activated receptor gamma in FPLD type 3; 4) lipid biosynthetic enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 in CGL type 1; 5) integral endoplasmic reticulum membrane protein seipin in CGL type 2; and 6) metalloproteinase ZMPSTE24 in MAD type B.