This report describes Hutchinson-Gilford progeria syndrome (HGPS). Most cases of HGPS are due to heterozygous de novo mutations, but it appears that autosomal dominant inheritance from a mosaic parent and autosomal recessive inheritance also occur. The human gene implicated in this disease is lamin A/C (LMNA), which encodes an intermediate filament protein that is a component of the nuclear lamina. There are multiple lamins in both humans and flies: the human genes LMNA, LMNB2 and LMNB1 are orthologous to fly genes Dmel\Lam and Dmel\LamC. Classical amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both fly genes. The human LMNA gene is implicated in multiple other diseases (see MIM:150330), including multiple form of muscular dystrophy (FBhh0000196) and dilated cardiomyopathy 1A (MIM:115200, FBhh0000157).
Multiple UAS and heat-shock constructs of the human Hsap\LMNA gene have been introduced into flies, including wild-type LMNA, mutant protein isoforms, and deletion constructs. HGPS is most commonly caused by the toxic accumulation of a truncated form of lamin A/C, called progerin, that has a deletion of 50 amino acids near the C terminus.
Variant(s) implicated in human disease tested (as transgenic human gene, LMNA): constructs with progerin C-terminal deletions have been characterized in flies (designated Hsap\LMNAprogerin.UAS.A and Hsap\LMNAΔ150.UAS). Variant(s) implicated in human disease tested (as analogous mutation in fly gene): E174K in the fly LamC gene (corresponds to E159K in the human LMNA gene); R564C in the fly LamC gene (corresponds to R527C in the human LMNA gene); these two variants described as associated with atypical HGPS.
Amorphic alleles of both Dmel\LamC and Dmel\Lam are lethal, usually in the larval or pupal stage. For hypomorphic alleles, surviving adults show reduced viability, locomotion defects, and various visible phenotypes. Genetic and physical interactions have been described for both genes; see below and in theLamC and Lam gene reports.
[updated Jan. 2018 by FlyBase; FBrf0222196]
Progeroid syndromes arecharacterized by the premature onset of age-related pathologies.
Progeria is characterized lipodystrophy or lipoatrophy, osteolysis, facial features resembling those of aged persons, and other characteristics associated with aging observed children or young adults. [from MIM:176670, MIM:614008; 2023.04.03]
[HUTCHINSON-GILFORD PROGERIA SYNDROME; HGPS](https://omim.org/entry/176670)
[LAMIN A/C; LMNA](https://omim.org/entry/150330)
Hutchinson-Gilford progeria syndrome encompasses a spectrum of clinical features that typically develop in childhood and resemble some features of accelerated aging. Although signs and symptoms vary in age of onset and severity, they are remarkably consistent overall. Children with Hutchinson-Gilford progeria syndrome (HGPS) usually appear normal at birth. Profound failure to thrive occurs during the first year. Characteristic facies, with receding mandible, narrow nasal bridge and pointed nasal tip develop. During the first to third year the following usually become apparent: partial alopecia progressing to total alopecia, loss of subcutaneous fat, progressive joint contractures, bone changes, nail dystrophy, and abnormal tightness and/or small soft outpouchings of the skin over the abdomen and upper thighs, and delayed primary tooth eruption. Later findings include low-frequency conductive hearing loss, dental crowding, and partial lack of secondary tooth eruption. Additional findings present in some but not all affected individuals include photophobia, excessive ocular tearing, exposure keratitis, and Raynaud phenomenon. Motor and mental development is normal. Death occurs as a result of complications of severe atherosclerosis, either cardiac disease (myocardial infarction) or cerebrovascular disease (stroke), generally between ages six and 20 years. Average life span is approximately 14.6 years. [from GeneReviews, Hutchinson-Gilford Progeria Syndrome, pubmed:20301300 2016.02.09]
Hutchinson-Gilford progeria syndrome is a rare disorder characterized by short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early death. Cognitive development is normal. Onset is usually within the first year of life (review by Hennekam, 2006, pubmed:16838330). The designation Hutchinson-Gilford progeria syndrome appears to have been first used by DeBusk (1972, pubmed:4552697). A subset of patients with heterozygous mutations in the LMNA gene and a phenotype similar to HGPS have shown onset of the disorder in late childhood or in the early teenage years, and have longer survival than observed in classic HGPS (Chen et al., 2003, pubmed:12927431; Hegele, 2003, pubmed:12927424). [from MIM:176670, 2016.02.09]
The most common mutations observed for HGPS are single nucleotide changes within codon 608 that create a cryptic splice site. The 3' portion of exon 11 is omitted when this splice occurs, resulting in a 50-aa near-terminal deletion and a protein product that lacks the site for endoproteolytic cleavage. [From UniProt, P02545; 2017.06.21]
Both classic infantile-onset and later childhood-onset Hutchinson-Gilford progeria syndrome (HGPS) can be caused by de novo heterozygous mutation in the lamin A gene (LMNA). Some familial cases have been documented; a number of these appear to be explained by germline mosaicism, and others by recessive inheritance. [from MIM:176670, 2016.06.21]
Fibroblasts from HGPS patients carrying the LMNA 1824C-T mutation, were found to have significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsened as the HGPS cells aged in culture, and their severity correlated with an apparent accumulation of mutant protein, designated LA delta-50. From this, it was concluded that expression of LA delta-50 has an age-dependent, cumulative, and ultimately devastating effect on nuclear architecture and function that is responsible for premature aging in HGPS patients (Goldman et al., 2004, pubmed:15184648). In cultured skin fibroblasts of patients with progeria, there is an increased fraction of heat-labile enzymes and other altered proteins (Goldstein and Moerman, 1978, pubmed:655163). [from MIM:176670, 2016.02.09]
HGPS is caused by the toxic accumulation of a truncated form of lamin-A/C. This mutant protein, called progerin (isoform 6), acts to deregulate mitosis and DNA damage signaling, leading to premature cell death and senescence. The mutant form is mainly generated by a silent or missense mutation at codon 608 of prelamin A that causes activation of a cryptic splice donor site, resulting in production of isoform 6 with a deletion of 50 amino acids near the C terminus. Progerin remains permanently farnesylated, thus, it cannot incorporate normally into the nuclear lamina (Eriksson et al., 2003, pubmed:12714972). [From UniProt, P02545; 2017.06.21]
The LMNA gene encodes lamin A and lamin C. 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 (see LMNB1; MIM:150340), and C, have been described in mammalian cells (Fisher et al., 1986, pubmed:3462705). [From MIM:150330, 2016.02.09]
Many to many: 3 human to 2 Drosophila.
Ortholog of human LMNB2, LMNA, and LMNB1 (2 Drosophila to 3 human).
Dmel\LamC shares 38% identity and 58% similarity with human LMNB2, 35% identity and 54% similarity with human LMNA, and 37% identity and 58% similarity with human LMNB1.
