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GENATLAS PHENOTYPE

last update : 28-09-2016

Symbol	PRO1
Location	1q22
Name	Hutchinson-Gilford progeria syndrome
Other name(s)	progeria
Corresponding gene	LMNA
Other symbol(s)	HGP1, HGPS
Main clinical features	precocious senility and premature death (mean lifespan of 13 year), including post natal growth retardation, micrognathia, absence of subcutaneous fat, alopecia, acro-osteolysis and premature atherosclerosis due to progressive vascular smooth muscle cell defects and calcifications of the vessel wall irregular dentin formation, caused severe dental abnormalities affecting the incisors
Genetic determination	autosomal dominant
Prevalence	1 in 4 million live births
Related entries	. including any atypical cases with generalized wasting, thinned skin and survival to relatively older age
Function/system disorder	dermatology
	osteo-articular
	neuromuscular
Type	disease

Gene product

Name

lamin A/C, progerin

Mechanism(s)

Gene mutation	Chromosome rearrangement	Effect	Comments

abnormal splicing		truncated protein	mutation G608G, activating an aberrant cryptic splice site in LMNA pre-mRNA, in the nuclear localization signal (NLS) or Ig fold domain, producing a truncated mutant protein, Delta50 lamin A, deleted from the C-terminal tail (AA 607–656) termed PROGERIN (become permanently anchored in the nuclear membrane, disrupting proper nuclear scaffolding and causing the characteristic nuclear blebbing), impairing functions specific for each lamin type such as nuclear membrane biogenesis, signal transduction, nuclearcompartmentalization and gene regulation

Remark(s)

relatively reduced telomere length in patients fibroblasts and stricking nuclear abnormalities , which may also play a key role in short replicative life span and /or an independent role in the pathogenesis

alterations in mitosis and cell cycle progression caused by the mutant Delta50 lamin A known to accelerate human aging

NEMO (IKBKG) shuttle may link genotoxic stress to the activation of innate immunity system and cause premature aging via inflamm-aging process

expression of progerin leads to alterations in nuclear morphology in keratinocyte that are reversed by inhibition of farnesyltransferasae, but epidermal expression does not lead to alopecia or other skin abnormalities

defects in the DNA repair machinery in patients suffering from progeroid syndromes due to expression of LAÄ50/progerin or abnormal levels of farnesylated pre-lamin A. (PMID: 17360326))

somatic cells from patients, despite their significant premature senescence phenotypes and nuclear defects, have been properly reprogrammed and can be effectively maintained in a pluripotent state (PMID: 21346760))

mutant acts as a dominant negative protein that changes the structure of the nuclear lamina, disrupts the nucleocytoplasmic RAN gradient and inhibits nuclear localization of UBE2I (PMID: 2167015)

mutation changes the accessibility of the 5 prime SS of LMNA exon 11 which is sequestered in a conserved RNA structure (PMID: 21875900))

cellular senescence of HGPS fibroblasts is corrected by depletion of SUN1 (PMID: 22541428))

mutation during osteoblast development results in loss of osteocytes, irregular mineralization, and poor biomechanical properties (PMID: 22893709))

lonafarnib therapy increased the rate of weight gain and improved measures of cardiovascular stiffness, bone structure, or audiological status (PMID: 23012407))

association with telomeres is impaired in PRO1, and this impaired interaction is central to disease since increasing TMPO levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas loweringTMPO levels exacerbates progerin-induced defects (PMID: 26312502))

Genotype/Phenotype correlations

homozygous loss-of-function mutation in the ZMPSTE24 gene and a heterozygous mutation in the LMNA gene with a C-terminal elongation of the final lamin, leading to progeria phenotype

severe forms of progeria caused by unusual mutations in LMNA, caused very frequent use of the same exon 11 splice donor site that is activated in typical form, and the ratios of progerin mRNA and protein to wild-type were higher than in typical form