DNA sequencing of LMNA in five Canadian FPLD probands indicated that each had a novel missense mutation, R482Q, which co-segregated with the FPLD phenotype and was absent from 2000 normal alleles ( P = 1.1 x 10(-13)).
It is still not at all clear how defects in these nuclear membrane proteins are related to the phenotype, even less clear that LMNA mutations can also be associated with familial dilated cardiomyopathy with no weakness, and even familial partial lipodystrophy with diabetes mellitus and coronary heart disease!
It also remains to be established whether the insulin resistance in FPLD is a consequence of the reduced plasma leptin or of another functional change resulting from mutant LMNA.
It also remains to be established whether the insulin resistance in FPLD is a consequence of the reduced plasma leptin or of another functional change resulting from mutant LMNA.
Because FPLD is an extreme example of genetically disturbed adipocyte differentiation, it is possible that common variation in LMNA is associated with obesity-related phenotypes.
Lamin A/C mutations cause the autosomal-dominant form of EDMD, limb-girdle muscular dystrophy with atrioventricular conduction disturbances (type 1B), hypertrophic cardiomyopathy and Dunnigan-type familial partial lipodystrophy.
Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together with the R582H heterozygous substitution recently described, confirms that the C-terminal region specific to the lamin A isoform is a second susceptibility region for mutations in FPLD.
Twenty-three different mutations of LMNA have so far been shown to cause autosomal-dominant Emery-Dreifuss muscular dystrophy (EDMD2), three mutations were reported to cause limb-girdle muscular dystrophy (LGMD1B), eight mutations are known to result in dilated cardiomyopathy (CMD1A), and seven mutations were reported to cause familial partial lipodystrophy (FPL).
Phenotypic heterogeneity in patients with familial partial lipodystrophy (dunnigan variety) related to the site of missense mutations in lamin a/c gene.
AS can be attributed to familial factors and that genetic variation in LMNA might not only underlie rare cases of FPLD, but may also contribute to variation in adipocyte size in the general population.
One form of lipodystrophy, namely Dunnigan-type familial partial lipodystrophy (FPLD) was shown to result from mutations in the LMNA gene, which encodes nuclear lamins A and C. Although the relationship between the mutations in the nuclear envelope and insulin resistance is unclear at present, these findings might eventually be shown to have relevance for the common insulin resistance syndrome and for drug-associated lipodystrophies.
Among the candidate genes to consider for the non-LMNA-associated forms of FPLD are other components of the inner nuclear membrane, such as lamin B1 and B2 and the lamin B receptor.
Among the candidate genes to consider for the non-LMNA-associated forms of FPLD are other components of the inner nuclear membrane, such as lamin B1 and B2 and the lamin B receptor.
Because familial partial lipodystrophy is an extreme example of genetically disturbed adipocyte differentiation, it is possible that common variation in LMNA is associated with obesity-related phenotypes.
Mutations in the LMNA gene, which encodes nuclear lamins A and C, underlie both Emery-Dreifuss muscular dystrophy (EMD2) and Dunnigan-type familial partial lipodystrophy (FPLD).