A Novel LMNA Mutation Causes Altered Nuclear Morphology and Symptoms of Familial Partial Lipodystrophy (Dunnigan Variety) with Progeroid Features

Abstract

Dunnigan-type partial lipodystrophy (familial partial lipodystrophy, Dunnigan variety, FPLD2) can be caused by LMNA mutations. We identified a novel heterozygous LMNA mutation, P485R, in a patient referred to the International Registry of Werner Syndrome because of features consistent with that of progeroid disorder but who was wild type at the WRN locus. The novel mutation is located 2 amino acids away from the canonical FPLD mutations in exon 8 of the LMNA gene. Immunocytochemical analysis revealed abnormal nuclear morphology characteristic of laminopathies within primary fibroblast cultures, but not in a lymphoblastoid cell line, in keeping with previous observations. Our findings indicate that FPLD2 should be considered in the differential diagnosis of the Werner syndrome.

Fig. 1

FPLD2 mutations in LMNA exon 8. a Detection of c.1455A>G (Pro485Arg) mutation. Chromatographs of LMNA exon 8 sequences are shown in forward (top) and reverse (bottom) directions. b Diagram of lamin A protein, showing the exon 8 region in globular tail domain. NLS = Nuclear localization signal. c Previously described FPLD2 mutation in LMNA exon 8. Only mutations reported to result in patients with typical FPLD2 phenotypes are indicated (amino acids coded by exon 8).

Fig. 2

Abnormal nuclear morphology and lamin A/C staining patterns in primary fibroblasts with the p.P485R mutation. Control fibroblasts (82-6), LMNA mutant fibroblasts (Registry VGS1010 with the p.P485R mutation and PORTU8010 with the p.R133L mutation) were stained for lamin A/C and counterstained with DAPI. Notice the irregular thickening and aggregates of nuclear lamina in the nuclei of LMNA mutant fibroblasts.