Hutchinson Gilford Progeria Syndrome

The Progeria syndrome, first described at the end of the 19th century by Jonathan Hutchinson (Hutchinson 1886) and later by Hastings Gilford (Gilford 1904), is a very rare and severe developmental disorder (its prevalence is about 1 in 4 to 8 million) characterized by the precocious appearance of pathologies which are typical of advanced age. The median age at diagnosis is 2 years. The clinical phenotype is characterized by an overall severe growth retardation (median final height = 100-110 cm; median final weight = 10-15 kg), usually associated to the following features:

- Skeletal alterations include: macrocephaly with craniofacial disproportion (frontal bossing, ectropion, small, low-set ears, micrognathism, long beaked nose, persistent fontanels, hypoplastic clavicles, generalized osteopenia/osteoporosis with repeated pathologic fractures (Khalifa 1989), acro-osteolysis of distal phalanges or clavicles, progressive joint stiffness, coxa valga with "horseback-riding" stance

- Generalized marked muscular dystrophy and atrophy is found, with pain of muscular origin

- Cutaneous changes include: generalized lipodystrophy with a thin, atrophic, dry and inelastic skin, presenting with sclerodermatous focal lesions (Jansen and Romiti 2000) and hyperpigmented zones. Cutaneous appendices become atrophic, giving rise to alopecia and absence of eyebrows. The venous superficial network is prominent, mainly on skull and thorax

- From a cardiovascular point of view, the patients present with precocious and extremely severe atherosclerosis, often cardiomyopathy, and death occurs at a median age of 13.5 years, in most cases due to myocardial infarction. The longest lifespan reported is 45 years. Premature subintimal fibrosis of great arteries has been reported (Baker et al. 1981; Ackerman et al. 2002)

- A variety of immunological abnormalities have been reported as well (Harjacek et al. 1990)

- Some cases presenting with very severe skeletal pathology have been reported (de Paula Rodrigues et al. 2002)

- The cognitive functions of the affected children are completely conserved

Not all of the aging processes are advanced in affected children: notably there's often a delayed dentition, cancer incidence is not augmented, dementia, cataract, or deafness are usually not observed.

The observed sex ratio of progeria is: M:F=1.2:1. No ethnic-specific recurrence has been reported in these patients.

Most of the typical Hutchinson-Gilford progeria cases are due to a recurrent, de novo point mutation in LMNA exon 11: c.1824C>T. This mutation is localized in the part of the gene specifically encoding lamin A. Its predicted effect is a silent amino acid change at codon 608 (p.G608G). In fact, this sequence variation is not silent, in that it occurs in a probable exon splicing enhancer (ESE, for review, see Cartegni et al. 2002), and is predicted to cause a reduced affinity for the ASF/SF2 splicing factor. In consequence, a cryptic splice site is activated in transcripts issued from the mutated allele, which is located 5' to the variation, between nucleotides 1818 and 1819 (Fig. 2a). Consequently, smaller, aberrant transcripts lacking the last 150 base pairs of exon 11 are produced, together with the wild type transcripts from the mutated allele. This phenomenon is described in the following way, according to standard international nomenclature: [r.1824C>T+r.1819_1968del] (De Sandre-Giovannoli et al. 2003; Eriksson et al. 2003). A quantification of the relative amounts of transcripts and proteins issued from mutated and wild type alleles was estimated by Reddel and colleagues. They showed that abnormally spliced (progerin) transcripts constituted 84.5% of the total mRNA derived from the mutant allele and 40% of all lamin A transcripts obtained from both alleles (Reddel and Weiss 2004).

In the deleted transcript, the reading frame is conserved, causing the appearance of a truncated Prelamin A precursor, also called progerin or laminA50, lacking amino acids 607 to 656 (p.V607_Q656del; De Sandre-Giovannoli et al. 2003; Eriksson et al. 2003).

This protein lacks the second cleavage site recognized by ZMPSTE24 during prelamin A post-translational processing, so that this truncated prelamin A precursor cannot undergo complete maturation. While it can undergo the first three processing steps, i.e., farnesylation, cleavage, and methylation, it cannot undergo the second cleavage, at the fourth processing step, likely maintaining farnesyl and methyl moieties on its C-terminal cysteine residue.

Activation of a cryptic splice Giy>Giy site between nt 1818 and

Fig. 2. a: Elecropherogram of LMNA exon 11 in a patient affected with Hutchinson-Gilford progeria, showing the heterozygous c.1824C>T transversion (p.608G). The schema shows the consequence of the mutation, consisting in the activation of a splice site located between coding nucleotides 1818 and 1819 in transcripts issued from the mutated allele. b: Western blot analysis with anti-human lamin A/C antibodies on fibroblast cultures issued from a patient affected with HGPS and carrying the heterozygous c.1824C>T transversion (p.G608G). Progerin, weighing about 68 kDa, migrates in proximity to lamin C

Progerin can be visualized in western blot studies from a patient's cultured cells (Fig. 2b) with antibodies directed against the N-terminal part of lamins A/C, as a 68 kDa protein migrating between lamins A (72 kDa) and C (64 kD).

It is of major importance to underscore here that the pathomechanism involved in progeria is thus not limited to an abnormal splicing event, which per se maintains in this case the reading frame and could potentially lead to the production of a partially functional protein product, but it is intimately linked to aberrant functional interactions of the truncated protein produced. Indeed, the deletion resulting from the aberrant splicing process prevents prelamin A precursors from interacting with one of its major post-translational processing enzymes, ZMPSTE24. Moreover, the truncated prelamin A produced from the deleted in-frame transcripts is not recognized by the cell as an aberrant product, so that its ubiquitination and proteasomal degradation are somehow prevented. It remains to be established if and how the probable farnesylated status of the protein is involved in the prevention of its degradation.

As we will discuss further on, it has subsequently been shown that:

1. The intranuclear, ubiquitous accumulation of this incompletely processed precursor exerts toxic, dominant negative effects on wild-type residual proteins (Goldman et al. 2004; Scaffidi and Misteli 2005; Fong et al. 2004)

2. These toxic effects are entirely reversible, under many measurable aspects, when the intranuclear amounts of precursors are reduced through different approaches (Scaffidi and Misteli 2005; Fong et al. 2004)

Indeed, the nuclei of HGPS patients' cultured cells show important alterations of morphology and composition, which increase with the number of passages, in correlation with an apparent increase of nuclear amounts of progerin (Bridger and Kill 2004; Goldman et al. 2004). Supporting the hypothesis of progerin's dominant negative effect, the same nuclear alterations can be induced by transfection of cDNAs encoding Progerin in wild-type cells (Goldman et al. 2004, Scaffidi and Misteli 2005).

Indirect immunofluorescence experiments with antibodies directed against lamins A/C or some of their molecular partners allow to observe nuclear blebs and herniations of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores (De Sandre-Giovannoli et al. 2003; Eriksson et al. 2003; Goldman et al. 2004). Some of these nuclear alterations, in different extents and percentages of cells, are observed as well in other laminopathies such as FPLD, EDMD, and MADA (Vigouroux et al. 2001; Favreau et al. 2003; Novelli et al. 2002).

From a clinical point of view, in our experience, it should be underlined that: while on one hand in children affected with highly typical Hutchinson-Gilford progeria, the LMNA c.1824C>T mutation (p.G608G) is very probably identified by molecular screening, on the other hand the presence of this mutation should not be excluded in patients presenting with neonatal progeroid features.

"Neonatal progeria" cases had been described before a molecular diagnosis was made available and were controversial. It was indeed discussed to which nosologic groups these patients should belong: whether they represented neonatal HGPS cases, Wiedemann-Rautenstrauch syndrome cases, or neither (Rodriguez et al. 1999a; Faivre et al. 1999; Rodriguez et al. 1999b). Recently, two papers have shown that children carrying - at least -the LMNA p.G608G mutation can present with very severe neonatal progeroid phenotypes (Navarro et al. 2004; Sevenants et al. 2005)

These observations obviously raise the question of the very likely influence of yet unidentified modifier genes or possibly epigenetic factors increasing the clinical severity. Interpersonal variations of the efficacy of splicing (i.e., mutated transcripts' aberrant or correct splicing) and, consequently, of the rate of production and global amounts of progerin produced, might also be one of the factors modulating the severity LMNA p.G608G phenotypes, ranging from typical HGPS, to neonatal progeria, to restrictive dermopathy.

In most cases the recurrent point c.1824C>T mutation is thought to occur de novo in maternal or paternal germ lines or in zygotes at an early developmental stage. A paternal effect had been hypothesized on the basis of advanced paternal age (DeBusk 1972; Jones et al. 1975) and has been reported by D'Apice and colleagues in 2004 (D'Apice et al. 2004). The description of sibs affected with HGPS, in the context of a majority of sporadic cases, had led to hypothesize the possibility of germinal mosaicism (DeBusk et al. 1972). One case of somatic and germinal mosaicism for the LMNA c.1824C>T mutation has recently been reported in the unaffected mother of a child affected with progeria (Wuyts et al. 2005).

At least 14 other lamin A/C mutations have been reported as causing progeroid phenotypes including mandibuloacral dysplasia (homozygous p.R527H; Novelli et al. 2002), progeria (heterozygous p.G608S, heterozygous p.E145K; Eriksson et al. 2003; compound heterozygous p.R471C and p.R527C; Cao and Hegele 2003; p.T623S, Fukuchi et al. 2004; homozygous p.K542N, Plasilova et al. 2004), atypical Werner syndrome (p.R133L, p.L140R, p.A57P, Chen et al. 2003; p.E578V, Csoka et al. 2004), atypical progeroid syndromes (heterozygous p.R644C, Csoka et al. 2004), Seip syndrome (heterozygous p.T10I, Csoka et al. 2004) and restrictive dermopathy (IVS11+1G>A, causing p.G567_ Q656del, which we will discuss further on). These are mostly localized in the lamin-A-specific C-terminal tail and in the N-terminal region. Of these mutations, only three have been reported to specifically alter lamin A splicing and lead to the production of truncated protein products (p.G608G, p.T623S and IVS11+1G>A; Fig. 3).

HGPS

r.1864_1968del p.V622_Q656del

HGPS

HGPS

35 aa del 50 aa del 90 aa del

(predicted p.T623S) (predicted p.G608G) (IVS11+1G>A)

r.1864_1968del p.V622_Q656del r.1819_1968del p.V607_Q656del r.1699_1968del p.G567_Q656del

Fig. 3. Schema showing the three different truncated prelamin A forms that have been associated with progeroid disorders. All the deletions are localized in prelamin A Carboxy-terminal globular tail and are due to LMNA mutations affecting the splicing of exon 11. NLS = nuclear localization signal; Ig fold = immunoglobulin fold

A few remarks should be made regarding two of these mutations:

- The heterozygous p.R133L mutation had previously been described in a patient affected with generalized acquired lipoatrophy, insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic car-diomyopathy with valvular involvement, and disseminated whitish papules (Caux et al. 2003)

- The heterozygous p.R644C mutation in lamin A/C had already been reported as being associated to a CMD1A phenotype (Genschel et al. 2001) and a LGMD1B phenotype, together with another variation affecting the same codon (R644H) (Mercuri et al. 2004)

In 2003, Agarwal and colleagues observed for the first time the involvement of ZMPSTE24/FACE-1 in the pathogenesis of a progeroid disorder: severe mandibuloacral dysplasia (MADB; Agarwal et al. 2003). The reported patient carried two compound heterozygous mutations: p.Trp340Arg and p.Leu362PhefsX19, caused by a frame-shifting insertion between coding nucleotides 1085 and 1086 (c.1085_1086insT).

In addition, as will be further discussed, mice inactivated for the Zmpste24 gene showed a series of phenotypic features recalling different laminopathies characterized by premature aging and death (Pendas et al. 2002; Bergo et al. 2002).

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