An inherited LMNA gene mutation in atypical Progeria syndrome

Abstract

Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

“…Given their common molecular bases linked to prelamin Adeficient processing, we propose to name this group of diseases "HGPS-like" syndromes. Conversely, a distinct group of premature aging syndromes called "Atypical Progeria Syndromes" (APS) are being delineated [177][178][179] (Fig. 2).…”

“…They are characterized by prelamin A-proficient processing and are due to the production of A-type lamins carrying specific missense mutations. They can be transmitted on a dominant or a recessive pattern of inheritance (see [177] for a recent review).…”

Physiological and Pathological Aging Affects Chromatin Dynamics, Structure and Function at the Nuclear Edge

“…The G608G mutation activates a cryptic splicing site that results in the deletion of 50 amino acids at the C terminus of pre-Lamin A, leading to production and accumulation in the nucleoplasm of a toxic protein called progerin; utlimately disrupting the integrity of the NE detectable as nuclear shape distorsions and blebbings (De Sandre-Giovannoli et al, 2003; Eriksson et al, 2003). Other LMNA mutations are associated with atypical progeroid syndromes, not systematically associated with progerin accumulation (Fukuchi et al, 2004; Moulson et al, 2007; Doubaj et al, 2012; Barthelemy et al, 2015) or MAD (Novelli et al, 2002). Recessive mutations in the ZMPSTE24 gene, encoding the Zinc Metallopeptidase STE24 that cleaves the prenylated and carboxy methylated 15-amino acid tail from the C-terminus of pre-Lamin A, are also associated with diseases that share features of accelerated aging such as MAD (Agarwal et al, 2003),or RD (Navarro et al, 2014).…”

Oxidative stress and antioxidant response in fibroblasts from Werner and Atypical Werner Syndromes

“…The AWS patients suffer the mutation of the lamin A/C gene ( LMNA/C ), the same causal gene seen in Hutchinson-Gilford progeria syndrome (HGPS) [19, 20]. Structural analyses have suggested the presence of missense and splicing mutations in LMNA -conserved residues [19] which principally affect exon 11 in this gene and correspond to the heptad repeat region of lamin A.…”

“…Some substitutions do not change the amino acids but lead to the weak activation of the same cryptic splicing site, like in Hutchinson-Gilford progeria syndromes. By contrast, others like the E578V mutation, are thought to alter the interaction of lamin A with other proteins, or interfere with protein-protein interactions (Supplementary Figure S1B) [19, 20]. Therefore, the causes of AWS are molecularly heterogeneous and have not been fully elucidated [17].…”