Familial partial lipodystrophy associated with compound heterozygosity for novel mutations in the LMNA gene

Savage, David B.; McFarlane, Ian G.; Barroso, Inês; Soos, Maria A.; Powlson, Andrew S; Thomas, E. Louise; Bell, Jimmy D.; Scobie, I N; Belchetz, P. E.; Kelly, William F.; Halsall, David; Schafer, Alan J.; O’Rahilly, Stephen

doi:10.1007/s00125-004-1360-4

Cited by 43 publications

(24 citation statements)

References 8 publications

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“…22 We also identified a single pathogenic variant in SLC7A9 in a 49-year-old man. The same variant is associated with dominant cystinuria in the stone-forming range; 24,25 stone formation is often prevented by adequate hydration and dietary modifications.…”

Section: Personal Genome Sequencing and Medical Annotationmentioning

confidence: 86%

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

Reuter

Walker²,

Thiruvahindrapuram³

et al. 2018

CMAJ

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Section: Personal Genome Sequencing and Medical Annotationmentioning

confidence: 86%

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

Reuter

Walker²,

Thiruvahindrapuram³

et al. 2018

CMAJ

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“…Depending on the context however, these mutations can cause disease: T528M or M540T alone appear non-pathogenic, but when inherited together, they result in an apparently typical HGPS but without prelamin A accumulation [32]. Certainly, a particular LMNA pathogenic mutation/SNP combination can increase the penetrance of a phenotype, which offers an explanation for intra-and inter-familiar variations [33], but may also alter the clinical condition diagnosed: while the S583L mutation normally causes FPLD2, when present with T528M it results in FPLD1 [34]. Modifying genes/SNPs are likely to explain inconclusive attempts to associate mutation with laminopathy (Figure 2c), where, for example, a single mutation has been reported to express phenotypic variability, such as with R60G, Y267C, R377H/L and R644C (Figure 1).…”

Section: Effect Of Modifying Genes and Snps (Single Nucleotide Polymomentioning

confidence: 95%

Genotype–phenotype correlations in laminopathies: how does fate translate?

Scharner

Gnocchi

Ellis

et al. 2010

Biochemical Society Transactions

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A-type laminopathies are a group of diseases resulting from mutations in the intermediate filament proteins lamin A and C (both encoded by the LMNA gene), but for which the pathogenic mechanisms are little understood. In some laminopathies, there is a good correlation between the presence of a specific LMNA mutation and the disease diagnosed. In others however, many different mutations can give rise to the same clinical condition, even though the mutations may be distributed throughout one, or more, of the three functionally distinct protein domains of lamin A/C. Conversely, certain mutations can cause multiple laminopathies, with related patients carrying an identical mutation even having separate diseases, often affecting different tissues. Therefore clarifying genotype-phenotype links may provide important insights into both disease penetrance and mechanism. In the present paper, we review recent developments in genotype-phenotype correlations in laminopathies and discuss the factors that could influence pathology.

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“…The control volunteer was a 38-year-old female (BMI, 24.2 kg/m 2 ), INSR A1135E was a 17-year-old female (BMI, 21.5 kg/m 2 ; patient 3 in Table 2), AKT2 R274H was a 40-year-old female (BMI, 26.7 kg/m 2 ; patient 5 in Table 2), and LMNA was a 45-year-old woman (BMI, 25.0 kg/m 2 with FPLD2; she was a compound heterozygote for LMNA S583L and T528M; ref. 40). VAT is shown in yellow.…”

Section: Figurementioning

confidence: 99%

Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis

Semple¹,

Sleigh²,

Murgatroyd³

et al. 2009

J. Clin. Invest.

215

256

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Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.

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Familial partial lipodystrophy associated with compound heterozygosity for novel mutations in the LMNA gene

Cited by 43 publications

References 8 publications

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

Genotype–phenotype correlations in laminopathies: how does fate translate?

Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis

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