Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is one of the most severe disorders among laminopathies—a heterogeneous group of genetic diseases with a molecular background based on mutations in the LMNA gene and genes coding for interacting proteins. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat, alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood. LMNA codes for two major, alternatively spliced transcripts, give rise to lamin A and lamin C proteins. Mutations in the LMNA gene alone, depending on the nature and location, may result in the expression of abnormal protein or loss of protein expression and cause at least 11 disease phenotypes, differing in severity and affected tissue. LMNA gene-related HGPS is caused by a single mutation in the LMNA gene in exon 11. The mutation c.1824C > T results in activation of the cryptic donor splice site, which leads to the synthesis of progerin protein lacking 50 amino acids. The accumulation of progerin is the reason for appearance of the phenotype. In this review, we discuss current knowledge on the molecular mechanisms underlying the development of HGPS and provide a critical analysis of current research trends in this field. We also discuss the mouse models available so far, the current status of treatment of the disease, and future prospects for the development of efficient therapies, including gene therapy for HGPS.
Highlights
Hutchison-Gilford progeria syndrome (HGPS; OMIM 176670) is a rare human genetic disorder linked with a subset of specific mutations in the LMNA gene, coding for lamin A and lamin C
Different sets of mutations in the LMNA gene and genes coding for interacting proteins, such as emerin (EMD/STA gene) and BAF, give rise to a variety of genetic disorders collectively called laminopathies [1,2,3]
If we consider such simple relocation to the nuclear lamina of a particular, single lamina associated domains (LADs) region we might predict that genes located in such a domain will be probably subjected to a different environment and be abnormally regulated since lamins are responsible for proper forparticular cell type, LADs formation, but through affecting LADs formation or not affect transcriptionally active domains (TADs)-TAD interactions and change gene expression profiles [87]
Summary
Hutchison-Gilford progeria syndrome (HGPS; OMIM 176670) is a rare human genetic disorder linked with a subset of specific mutations in the LMNA gene, coding for lamin A and lamin C proteins. Different sets of mutations in the LMNA gene and genes coding for interacting proteins, such as emerin (EMD/STA gene) and BAF (barrier-to-autointegration, BANF1 gene), give rise to a variety of genetic disorders collectively called laminopathies [1,2,3]. It is currently thought that at least 11 distinct disease phenotypes can be defined within the laminopathy group Cells 2019, 8, 88 with ZMPSTE24 gene coding for cysteine proteinase (prenyl protease 1 homolog), which among other functions, is responsible for maturation of prelamin A by cleaving off the farnesylated C-terminus. RD is an autosomal recessive, lethal disorder associated with mutations in two genes: LMNA and ZMPSTE24 [10,11]
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