NM_170707.3(LMNA):c.398G>T (p.Arg133Leu) AND Familial partial lipodystrophy 2

Clinical significance:Pathogenic (Last evaluated: Dec 1, 2005)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000015577.29

Allele description [Variation Report for NM_170707.3(LMNA):c.398G>T (p.Arg133Leu)]

NM_170707.3(LMNA):c.398G>T (p.Arg133Leu)

Gene:
LMNA:lamin A/C [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q22
Genomic location:
Preferred name:
NM_170707.3(LMNA):c.398G>T (p.Arg133Leu)
HGVS:
  • NC_000001.11:g.156130658G>T
  • NG_008692.2:g.53086G>T
  • NM_005572.3:c.398G>T
  • NM_170707.3:c.398G>T
  • NM_170708.3:c.398G>T
  • NP_005563.1:p.Arg133Leu
  • NP_733821.1:p.Arg133Leu
  • NP_733822.1:p.Arg133Leu
  • LRG_254t1:c.398G>T
  • LRG_254:g.53086G>T
  • LRG_254p1:p.Arg133Leu
  • LRG_254p2:p.Arg133Leu
  • LRG_254p3:p.Arg133Leu
  • NC_000001.10:g.156100449G>T
  • NM_170707.2:c.398G>T
  • P02545:p.Arg133Leu
Protein change:
R133L; ARG133LEU
Links:
UniProtKB: P02545#VAR_016913; OMIM: 150330.0027; dbSNP: 60864230
NCBI 1000 Genomes Browser:
rs60864230
Molecular consequence:
  • NM_005572.3:c.398G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial partial lipodystrophy 2 (FPLD2)
Identifiers:
MedGen: C1720860; Orphanet: 2348; OMIM: 151660

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000035842OMIMno assertion criteria providedPathogenic
(Dec 1, 2005)
germlineliterature only

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy.

Brown CA, Lanning RW, McKinney KQ, Salvino AR, Cherniske E, Crowe CA, Darras BT, Gominak S, Greenberg CR, Grosmann C, Heydemann P, Mendell JR, Pober BR, Sasaki T, Shapiro F, Simpson DA, Suchowersky O, Spence JE.

Am J Med Genet. 2001 Sep 1;102(4):359-67.

PubMed [citation]
PMID:
11503164

Drawing the line in progeria syndromes.

Hegele RA.

Lancet. 2003 Aug 9;362(9382):416-7. No abstract available.

PubMed [citation]
PMID:
12927424
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000035842.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (7)

Description

In a male patient whose phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, and hepatic steatosis (151660), Caux et al. (2003) found a heterozygous 398G-T transversion in exon 2 of the LMNA gene that resulted in an arg-to-leu change at codon 133 (R133L) in the dimerization rod domain of lamins A and C. The patient also had hypertrophic cardiomyopathy with valvular involvement and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadened the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the possibility of hypertrophic cardiomyopathy and skin involvement.

In 2 unrelated persons with a progeroid syndrome (see 176670), Chen et al. (2003) found heterozygosity for the R1333L mutation in the LMNA gene. One was a white Portuguese female who presented at the age of 9 years with short stature. She showed scleroderma-like skin changes and graying/thinning of hair. Type 2 diabetes developed at the age of 23 years. Hypogonadism, osteoporosis, and voice changes were also present. The other patient was an African American female in whom the diagnosis of a progeroid syndrome was made at the age of 18 years. Scleroderma-like skin, short stature, graying/thinning of hair, and type 2 diabetes at the age of 18 years were features. The deceased father, paternal aunt, and paternal grandmother of this patient were also diagnosed with severe insulin-resistant diabetes mellitus, suggesting that the R133L mutation might have been paternally inherited. It is noteworthy that a substitution in the same codon, R133P (150330.0032), was reported in a 40-year-old patient with Emery-Dreifuss muscular dystrophy who had disease onset at age 7 years and atrial fibrillation at age 32 years (Brown et al., 2001). Although Chen et al. (2003) designated these patients as having 'atypical Werner syndrome' (277700), Hegele (2003) suggested that the patients more likely had late-onset Hutchinson-Gilford progeria syndrome.

Vigouroux et al. (2003) emphasized that a striking feature in the patient reported by Caux et al. (2003) was muscular hypertrophy of the limbs, which contrasts with the muscular atrophy usually present in Werner syndrome. Muscular hypertrophy, along with insulin-resistant diabetes and hypertriglyceridemia, is more often associated with LMNA-linked Dunnigan lipodystrophy. Fibroblasts from their patient showed nuclear abnormalities identical to those described in Dunnigan lipodystrophy (Vigouroux et al., 2001).

Jacob et al. (2005) studied the pattern of body fat distribution and metabolic abnormalities in the 2 patients with atypical Werner syndrome described by Chen et al. (2003). Patient 1, an African American female, had normal body fat (27%) by dual energy X-ray absorptiometry (DEXA). However, magnetic resonance imaging (MRI) revealed relative paucity of subcutaneous fat in the distal extremities, with preservation of subcutaneous truncal fat. She had impaired glucose tolerance and elevated postprandial serum insulin levels. In contrast, patient 2, a Caucasian female, had only 11.6% body fat as determined by DEXA and had generalized loss of subcutaneous and intraabdominal fat on MRI. She had hypertriglyceridemia and severe insulin-resistant diabetes requiring more than 200 U of insulin daily. Skin fibroblasts showed markedly abnormal nuclear morphology compared with those from patient 1. Despite the deranged nuclear morphology, the lamin A/C remained localized to the nuclear envelope, and the nuclear DNA remained within the nucleus. Jacob et al. (2005) concluded that atypical Werner syndrome associated with an R133L mutation in the LMNA gene is phenotypically heterogeneous. Furthermore, the severity of metabolic complications seemed to correlate with the extent of lipodystrophy.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 21, 2017