Biomedical subjects

Olivier Lascols

Publications and source records attributed to Olivier Lascols.

4 recordsLinked to original sources

PubMed2025

Insulin receptor variants: Extending the traditional Mendelian spectrum.

PURPOSE: INSR encodes the insulin receptor, the essential entrainer of growth and metabolism to nutritional cues. INSR variants cause a spectrum of monogenic insulin resistance (IR) syndromes, namely, type A insulin resistance, Rabson-Mendenhall, and Donohue syndromes. However, to our knowledge, no large cohort studies focused on variant classification and its diagnostic value have been described. METHODS: This multicentric cohort study included 73 patients carrying INSR variants, referred for IR by 52 centers from 6 countries. Variants were classified using new bioinformatic tools relying on different prediction mechanisms and the American College of Medical Genetics and Genomics guidelines. RESULTS: Besides expanding the INSR mutational spectrum, this study suggested a semidominant inheritance in several Donohue/Rabson-Mendenhall syndrome families. Questioning strictly Mendelian inheritance, heterozygous loss-of-function (LoF) variants were mostly found in overweight patients, with a higher LoF frequency in IR patients than in the general population (odds ratio 5.77). Diagnostic challenges arose when trying to refine classification criteria for variants of uncertain significance. Among the variant effect predictors assessed, MISTIC and AlphaMissense outperformed REVEL. CONCLUSION: The spectrum of INSR-related disorders extends beyond traditional entities. Heterozygous INSR LoF variants may increase IR susceptibility. International collaboration and functional assays are needed to drive precision medicine forward.

Humans↗

PubMed2006

[Lipodystrophic syndromes: congenital or acquired diseases of adipose tissue].

Lipodystrophic syndromes regroup a heterogeneous group of genetic or acquired diseases. Lipodystrophy, an altered development and/or repartition of body fat, is associated with alterations of lipid and glucose metabolism with insulin resistance. Genetic forms, rare, can be generalized and recessive resulting from mutations in the seipin or AGPAT2 gene. Partial lipodystrophies are dominant and observed in patients mutated in the gene encoding PPAR-gamma or lamin A/C, a gene seen also mutated in patients with syndromes of premature aging. Acquired forms are common and regroup the highly prevalent Metabolic Syndrome, hypercorticism together with lipodystrophy related to antiretroviral treatment of HIV-infected patients.

Adipose Tissue↗

PubMed2005

Type A insulin resistance syndrome revealing a novel lamin A mutation.

Particular forms of polycystic ovary syndrome with severe hyperandrogenism, acanthosis nigricans, and marked insulin resistance, defining the type A insulin resistance syndrome, are due to insulin receptor gene mutations. However, the majority of affected individuals do not have such mutation, arguing for the genetic heterogeneity of this syndrome. The familial partial lipodystrophy of the Dunnigan type, one of the diseases due to mutations in the lamin A/C (LMNA) gene, is characterized by a lipodystrophic phenotype and shares some clinical and metabolic features with the type A syndrome. We describe here the case of a nonobese 24-year-old woman affected with type A syndrome without clinical lipodystrophy. We linked this phenotype to a novel heterozygous missense mutation in the LMNA, predicting a G602S amino acid substitution in lamin A. This mutation cosegregated with impaired glucose tolerance, insulin resistance, and acanthosis nigricans in the absence of clinical lipodystrophy in the family. The skin fibroblasts from the proband exhibited nuclear alterations similar to those described in other laminopathies, and showed several defects in the insulin transduction pathway. This study further extends the vast range of diseases linked to LMNA mutations and identifies another genetic cause for the type A insulin resistance syndrome.

Adult↗

PubMed2003

Prevalence of mutations in AGPAT2 among human lipodystrophies.

Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients' cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL patients from 30 families with mutations in AGPAT2. Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies, including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and AGPAT2 are the two major genes involved in the etiology of BSCL.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗