Mutations Involved in Premature-Ageing Syndromes

Figures & data

Table 1 Main Characteristics of the Premature-Ageing Syndromes Described in the Article

Disease	Causative Gene	Onset	Main Clinical Features
RD	ZMPSTE24: recessive null mutations	Neonatal	Intrauterine growth retardation, reduced fetal movements and pre-term delivery. Tight and translucent skin with erosions, facial dysmorphism, skeletal malformations, generalized arthrogryposis. Lethal within the first weeks of life.
HGPS	LMNA: de novo dominant point mutation (c.1824C>T; p.G608G)	Early childhood	Severe failure to thrive in infancy. Progressive alopecia leading to total alopecia. Skin lesions. Characteristic facies. Loss of subcutaneous fat. Bone changes. Skeletal anomalies. Musculoskeletal degeneration. Hearing loss. High-pitched voice. Delayed and crowded dentition. Atherosclerosis. Cerebrovascular disease. Death in mid teens from myocardial infarction or stroke (from vascular diseases).
MADB	ZMPSTE24: recessive mutations: often compound heterozygous mutations with a null allele and one maintaining some residual activity	Early childhood	Generalized lipodystrophy, altered skin pigmentation, alopecia, severe bone and growth defects.
MADA	LMNA: recessive missense mutations	Early childhood	Partial lipodystrophy at torso and limbs, bone abnormalities, altered skin pigmentation, lipodystrophic signs and mildly accelerated ageing.
NGPS	BANF1: recessive mutation (c.34G>A; p.Ala12Thr)	Early childhood	Failure to thrive, aged appearance, growth retardation, decreased subcutaneous fat, thin limbs, stiff joints, severe osteolysis, absence of early cardiovascular impairment.
MDPL	POLD1: dominant mutations, including the common de novo mutation (c.1812_1814delCTC, p.Ser605del) observed in 80% of the patients	Early childhood	Mandibular hypoplasia, prominent loss of subcutaneous fat, progeroid appearance, skin abnormalities, metabolic abnormalities including insulin resistance and diabetes mellitus, sensorineural deafness, hypogonadism in males.
MADaM	MTX2: recessive mutations	Early childhood	Small viscerocranium with mandibular underdevelopment, growth retardation, lipodystrophy, altered skin pigmentation, distal acro-osteolyses, renal focal glomerulosclerosis, severe cardiovascular disease.
Atypical progeroid laminopathies	LMNA and ZMPSTE24	Variable from early life to adulthood	Several LMNA mutations, including dominant and recessive ones result in a spectrum of progeroid laminopathies ranging in severity from severe RD-like forms to adult-onset atypical WS. Atypical (severe) MADB forms can result from recessive ZMPSTE24 mutations.
WS	WRN: recessive null mutations	Adulthood	Lack of the pubertal growth spurt during early teen years. Graying or loss of hair. Scleroderma-like skin lesions. Characteristic facies. Bilateral cataracts. Type 2 diabetes mellitus. Hypogonadism. Skin ulcers. Osteoporosis. Arteriosclerosis. Increased risk of cancer.

Abbreviations: HGPS, Hutchinson–Gilford progeria syndrome; MADA, mandibuloacral dysplasia type A; MADB, mandibuloacral dysplasia type B; MADaM, mandibuloacral dysplasia associated to MTX2; MDPL, mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome; NGPS, Néstor-Guillermo progeria syndrome; RD, restrictive dermopathy; WS, Werner syndrome.

Figure 1 Schematic representation of prelamin A processing in normal individuals, and in patients with Hutchinson–Gilford progeria syndrome and restrictive dermopathy. Notes: Adapted from Coppedè F. The epidemiology of premature aging and associated comorbidities. Clin Interv Aging. 2013;8:1023–1032.⁵© 2013 Coppedè. Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). In cells from healthy individuals, prelamin A undergoes a four-step process to become a mature lamin A, including (1) farnesylation of the cysteine residue on the C-terminal CaaX motif by a farnesyltransferase (FTASE), (2) cleavage of the –aaX terminal residues that can be performed either by RCE1 (Ras converting enzyme 1) or by ZMPSTE24 (Zinc metalloprotease related to Ste24p), (3) carboxymethylation of the C-terminal cysteine residue by ICMT (isoprenylcysteine carboxyl methyltransferase), (4) removal of the C‑terminal 15 residues through cleavage by ZMPSTE24. In Hutchinson–Gilford progeria syndrome (HGPS) the common LMNA (p.G608G) mutation results in the deletion of a 50aa region from prelamin A (in orange) containing the upstream ZMPSTE24 cleavage site, resulting in a shorter farnesylated protein that cannot undergo the last maturation step, termed progerin. In restrictive dermopathy (RD) recessive null mutations of ZMPSTE24 result in lack of ZMPSTE24 activity with subsequent accumulation of uncleaved and farnesylated lamin A precursors.

Coppedè F. The epidemiology of premature aging and associated comorbidities. Clin Interv Aging. 2013;8:1023–1032. doi:10.2147/CIA.S37213

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