"Laminopathies": a wide spectrum of human diseases

Abstract

Mutations in genes encoding the intermediate filament nuclear lamins and associated proteins cause a wide spectrum of diseases sometimes called "laminopathies." Diseases caused by mutations in LMNA encoding A-type lamins include autosomal dominant Emery-Dreifuss muscular dystrophy and related myopathies, Dunnigan-type familial partial lipodystrophy, Charcot-Marie-Tooth disease type 2B1 and developmental and accelerated aging disorders. Duplication in LMNB1 encoding lamin B1 causes autosomal dominant leukodystrophy and mutations in LMNB2 encoding lamin B2 are associated with acquired partial lipodystrophy. Disorders caused by mutations in genes encoding lamin-associated integral inner nuclear membrane proteins include X-linked Emery-Dreifuss muscular dystrophy, sclerosing bone dysplasias, HEM/Greenberg skeletal dysplasia and Pelger-Huet anomaly. While mutations and clinical phenotypes of "laminopathies" have been carefully described, data explaining pathogenic mechanisms are only emerging. Future investigations will likely identify new "laminopathies" and a combination of basic and clinical research will lead to a better understanding of pathophysiology and the development of therapies.

Figure 1

Schematic diagram of the nuclear envelope showing localizations and interactions of various proteins. Boxes highlight diseases caused by mutations in genes encoding the proteins indicated. RD: restrictive dermopathy, HGPS: Hutchinson-Gilford progeria syndrome, PHA: Pelger-Huet anaomaly, EDMD: Emery-Dreifuss muscular dystrophy, ADLD: Adult onset autosomal dominant leukodystrophy, BSS: Barraquer-Simons syndrome, LGMD: limb-girdle muscular dystrophy; DCM: dilated cardiomyopathy; CMT: Charcot-Marie-Tooth, FPLD: familial partial lipodystrophy, MADA / MADB: mandibuloacral dysplasia, WNR: Werner syndrome. For more specific disease nomenclature, see Table 1, Table 2 and Table 3.

Figure 2

Graph showing number of diseases caused by mutations in genes encoding nuclear lamins or associated proteins reported (y-axis) versus year (x-axis). Emerin, which is mutated in X-linked EDMD, was localized to the nuclear envelope in 1996. LMNA mutations were reported to cause autosomal dominant EDMD in 1999. In 2000, LMNA mutations were reported to cause autosomal recessive EDMD, cardiomyopathy dilated 1A, limb girdle muscular dystrophy type 1B and Dunnigan-type familial partial lipodystrophy. In 2002, LMNA mutations were reported to cause mandibulacral dysplasia and Charcot-Marie-Tooth disorder type 2B1 and mutations in LBR were reported to cause Pelger-Huet anomaly. In 2003, LMNA mutations were reported to cause Hutchinson-Gilford progeria syndrome, atypical Werner syndrome and lipoatrophy with diabetes, hepatic steatosis, hypertrophic cardiomyopathy and leukomelanodermic papules; LBR mutations were reported in HEM/Greenberg dysplasia; ZMPSTE24 reported in mandibulacral dysplasia and mutation in the gene encoding Aladin reported in triple A syndrome. In 2004, mutations in torsinA that cause DYT1 dystonia were reported to lead to abnormal protein localization in the perinuclear space, LMNA mutations were reported to cause restrictive dermopathy and LEMD3 mutations to cause Buschke-Ollendorff Syndrome and related sclerosing bone dysplasias. In 2005, ZMPSTE24 mutations were reported to cause a progeria syndrome and restrictive dermopathy; Lap2α polymorphisms were reported in two siblings with dilated cardiomyopathy. In 2006, duplication of LMNB1 was reported to cause adult- onset, autosomal dominant leukodystrophy and mutations in LMNB2 Barraquer-Simons syndrome. In 2007, mutations in SYNE1 were reported to cause a form of cerebellar ataxia.

Figure 3

Spectrum of disease-causing LMNA mutations. Schematic representations of lamin A and lamin C are shown. Portions of the proteins affected by LMNA mutations identified causing different diseases are indicated. Dominant disorders due to heterozygous LMNA mutations are depicted on the top and recessive disorders due to homozygous mutations are presented below (for more details, see UMD-LMNA mutation database at http://www.umd.be). Numbers in parentheses in black next to each disease acronym indicate the numbers of reported individuals carrying that LMNA mutation and presenting the corresponding phenotype. Figure is updated from Broers J, Ramaekers F, Bonne G, Hutchison C. The nuclear lamins: laminopathies and their role in premature ageing. Physiological Reviews 2006;86:967–1008 (used with permission).

Figure 4

Summary of potential pathogenic mechanisms resulting from mutations in LMNA and ZMPSTE24. See text for details.