Hereditary Syndromes with Signs of Premature Aging

Abstract

Background: Segmental progeroid syndromes (SPS) are rare hereditary diseases in which the affected individuals show signs of premature aging in more than one organ or type of tissue. We review the clinical and genetic features of some of these syndromes and discuss the extent to which their study affords a complementary opportunity to study aging processes in general.

Methods: This review is based on publications retrieved by a selective search in PubMed.

Results: Segmental progeroid syndromes are a clinically and genetically heterogeneous group of hereditary diseases. They can be categorized, for example, by the age of onset of manifestations (congenital vs. infantile vs. juvenile/adult forms). They are diagnosed on clinical grounds supplemented by genetic testing on the basis of next-generation sequencing, which is of central importance in view of the marked heterogeneity and complexity of their overlapping clinical features. The elucidation of the genetic and molecular causes of these diseases can lead to causally directed treatment, as shown by the initial clinical trials in Hutchinson- Gilford progeria syndrome. The molecular features of SPS are identical in many ways to those of "physiological" aging. Thus, studying the molecular mechanisms of SPS may be helpful for the development of molecularly defined treatment approaches for age-associated diseases in general.

Conclusion: Segmental progeroid syndromes are a complex group of diseases with overlapping clinical features. Current research efforts focus on the elucidation of the molecular mechanisms of these diseases, most of which are very rare. This should enable the development of treatments that might be applicable to general processes of aging as well.

Figure

Pathogenesis of Hutchinson–Gilford progeria syndrome. The LMNA gene, which encodes lamin A (a structural protein of the nuclear membrane), contains 12 exons. The correctly spliced pre-messenger RNA (mRNA) results in lamin A which contains a detection site and cleavage site for the ZMPSTE24 enzyme within exon 11. The c.1824C>T mutation in exon 11, which is the cause of Hutchinson–Gilford progeria syndrome, activates a cryptic splicing site and causes an aberrant splicing event, removing 150 nucleotides (i.e. exactly 50 amino acids) from the mRNA. The post-translational protein modification normally consists of four steps: (1) A farnesyl group is attached by farnesyl transferase to the cysteine of the C-terminal CAAX box. (2) The last three amino acid residues are proteolytically cleaved by ZMPSTE24. (3) Carboxymethylation by ICMT. (4) The 15 C-terminal amino acids, including the farnesylated and carboxymethylated cysteine, are cleaved by ZMPSTE24. Since progerin lacks the detection site and cleavage site for the ZMPSTE24 enzyme, the second cleavage cannot occur; thus, the last 15 C-terminal amino acids, including the farnesylated cysteine are retained. As the result, progerin is permanently anchored in the nuclear membrane, influencing various cellular processes. Important progerin-associated cellular effects are shown in the Figure. Lonafarnib, a farnesyltransferase inhibitor, blocks the first step of posttranslational modification, the farnesylation. Therefore, progerin generally remains in the nucleoplasm and is hardly bound to the nuclear membrane; consequently, its effects are mitigated (adapted from [24]).