Laminopathies, other progeroid disorders, and aging: Common pathogenic themes and possible treatments

In this issue of the Journal, McPherson et al. [2009] describe a unique constellation of clinical findings—including premature ovarian failure and dilated cardiomyopathy—found in association with either of two adjacent missense mutations in LMNA, the gene which encodes the nuclear lamina proteins lamin A and lamin C. Remarkably,mutations inLMNAhave already been associatedwith at least 10 syndromes, encompassing a wide variety of phenotypes, including several specific myopathies, the dramatic ‘‘premature aging’’ phenotype of the Hutchinson–Gilford progeria syndrome (HGPS), and the distinct progeroid disorder of ‘‘atypical Werner syndrome. ’’ The complex, imperfect, and still emerging genotype–phenotype correlations for these ‘‘laminopathies’’ have been reviewed by others [Capell and Collins, 2006; Rankin and Ellard, 2006] and probably reflect themany ways that alterations of the nuclear lamina can affect nuclear shape, chromatin structure, and gene expression. Essentially, McPherson and her colleagues are reporting a new, albeit very rare, laminopathy syndrome, one characterized by a unique combination of premature ovarian failure, dilated cardiomyopathy, lipodystrophy, and progressive facial and skeletal changes, including micrognathia and sloping shoulders. These patients also develop a somewhat progeroid appearance. In fact, a possible diagnosis of Werner syndrome (OMIM# 277700) was considered for Patient 2, but later disproved [Nguyen et al., 2007]; and the third patient was originally reported as a case of atypical Werner syndrome [Chen et al., 2003]. In concluding their article, McPherson et al. suggest the possibility that LMNA mutations might be found in some patients previously diagnosed withMalouf syndrome, which comprises dilated cardiomyopathy and hypergonadotropic hypogonadism, and is of unknown genetic etiology [Malouf et al., 1985; Narahara et al., 1992; Gursoy et al., 2006]. This report of a new laminopathy comes at a very exciting time in the study of HGPS and other progeroid disorders, and should inspire some further reflection on these disorders, their possible relationships to natural aging, and the potential development of new treatments. Specifically, we should ask:What are the progeroid disorders? How are they related to natural aging? And, what, if anything, can we do to treat them? Despite the existence of hundreds of Mendelian disorders that can cause children to look frail or to die prematurely, very few of these conditions give a marked impression of ‘‘premature aging. ’’ In fact, a search of the OMIM database for the terms ‘‘premature aging,’’ ‘‘progeria,’’ ‘‘progeroid,’’ or ‘‘progeric,’’ together with a review of the section on disorders having a ‘‘SenileLike Appearance’’ in Smith’s Recognizable Patterns of Human Malformation [Jones, 2006], yields a list of only about 20 disorders described using one of these terms. Mutations in specific genes are known for 12 of these progeroid syndromes (Table I). The molecular etiologies remain unknown for the others, including some interesting entities, such as Wiedemann–Rautenstrauch syndrome (i.e., neonatal progeroid syndrome, OMIM# 264090) and Mulvihill–Smith syndrome (i.e., progeroid short stature with pigmented nevi, OMIM# 176690). Surprisingly, as shown in Table I, a classification of the 12 human progeroid syndromes of known genetic etiology into pathogenic categories, based on the major known function of each gene involved, suggests that 11 of these 12 disorders fall into just two broad groups: laminopathies and DNA repair disorders. The exception is the rare progeroid form of Ehlers–Danlos syndrome, which is due tomutations in theXGPT1 gene, causing an enzymatic defect in proteoglycan synthesis [Okajima et al., 1999]. The known progeroid laminopathies result frommutations in LMNA, LMNB2, or ZMPSTE24 (which encodes a protease required for prelamin A processing). The progeroid DNA repair diseases include Cockayne syndrome, trichothiodystrophy, XFE progeroid syndrome,Werner syndrome, Rothmund–Thomson syndrome, and ataxia telangiectasia. Although many questions remain about the pathogenic mechanisms of each of these disorders, and many of the mutated