Single-nucleotide polymorphisms of the nuclear lamina proteome

Abstract

Familial partial lipodystrophy (FPLD) has been shown to be due to mutations in the LMNA gene encoding nuclear lamins A and C, indicating that defective structure of the nuclear envelope can produce this unique phenotype. Some patients with inherited partial lipodystrophy have normal LMNA coding, promoter, and 3'-untranslated region sequences. This suggests that the FPLD phenotype is genetically heterogeneous. 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. We developed amplification primers for the coding regions of LMNB1, LMNB2, and LBR, which encode lamin B1, lamin B2, and the lamin B receptor, respectively. We found no putative disease mutations in any of these proteins in subjects with non-LMNA FPLD, but, through the screening of diseased and normal subjects, we identified several single-nucleotide polymorphisms (SNPs); specifically, five SNPs in LMNB1 and four SNPs in LBR. The LMNB2 gene was monomorphic in screening experiments. We conclude that mutations in other constituent proteins of the nuclear envelope are not present in subjects with non-LMNA-associated FPLD. However, the identification of amplification primers and SNPs provides tools to investigate these proteins for their association with other phenotypes.

Sequencing of the Reannotated LMNB2 Gene Reveals Novel Mutations in Patients with Acquired Partial Lipodystrophy

“…In 2001, we used the genomic information available at that time to develop amplification primers for candidate genes encoding nuclear envelope proteins, including LBR, LMNB1, and LMNB2 (MIM 150341), which encode lamin B receptor, lamin B1, and lamin B2, respectively. 7 We then sequenced these candidate genes in patients with AGL or APL who had no mutations in LMNA. 7 Although we identified several common polymorphisms, we found no disease-causing mutations and concluded that sequence variants affecting the nuclear lamina proteome were not likely to be associated with APL or AGL.…”

“…7 We then sequenced these candidate genes in patients with AGL or APL who had no mutations in LMNA. 7 Although we identified several common polymorphisms, we found no disease-causing mutations and concluded that sequence variants affecting the nuclear lamina proteome were not likely to be associated with APL or AGL. 7 Recent observations suggest that early versions of mammalian genome maps underestimated the total numbers of exons.…”

Barraquer–Simons syndrome: A rare clinical entity

“…To resolve whether Barraquer–Simons syndrome had a component of genetic susceptibility [Misra et al, ], candidate gene sequencing approach was used to identify genomic DNA sequence mutations that were present in patients with Barraquer–Simons syndrome but absent in healthy individuals. For this purpose, candidate genes encoding nuclear envelope proteins including LBR , LMNB1 , LMNB2 , which encode lamin B receptor, lamin B1, and lamin B2, respectively were sequenced [Hegele et al, ]. These candidate genes were also sequenced in patients with Barraquer–Simons syndrome who had no mutations in LMNA [Hegele et al, ].…”

“…For this purpose, candidate genes encoding nuclear envelope proteins including LBR , LMNB1 , LMNB2 , which encode lamin B receptor, lamin B1, and lamin B2, respectively were sequenced [Hegele et al, ]. These candidate genes were also sequenced in patients with Barraquer–Simons syndrome who had no mutations in LMNA [Hegele et al, ]. No disease‐causing mutations were found and it was concluded that sequence variants affecting the nuclear lamina proteome were not likely to be assicoated with Barraquer–Simons syndrome [Hegele et al, ].…”

“…These candidate genes were also sequenced in patients with Barraquer–Simons syndrome who had no mutations in LMNA [Hegele et al, ]. No disease‐causing mutations were found and it was concluded that sequence variants affecting the nuclear lamina proteome were not likely to be assicoated with Barraquer–Simons syndrome [Hegele et al, ]. However, upon revisiting the reannotated genomic structures of nuclear proteome genes [Frey et al, ], it was revealed that LMNB2 with only 6 exons identified in 2001 had actually 12 exons [Hegele et al, ].…”