LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

Florwick, Alyssa; Dharmaraj, Tejas; Jurgens, Julie A; Valle, David; Wilson, Katherine L.

doi:10.3389/fgene.2017.00079

Cited by 16 publications

(19 citation statements)

References 97 publications

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“…However, since there were no chromosomal deletions on SNP arrays and exome sequencing, and none of the other genes with rare homozygous variants in the affected sisters has a known association with intellectual impairment (online supplementary table S1), there is a strong likelihood that the homozygous p.R545H LMNA mutation caused developmental delay. The arginine residue at position 545 lies in the immunoglobulin fold of globular tail domain (residues 436–552) of lamins A and C 15–17. Such immunoglobulin folds are known for protein-protein interaction, which could be disrupted with the substitution of arginine for histidine at position 545.…”

Section: Discussionmentioning

confidence: 99%

A novel autosomal recessive lipodystrophy syndrome due to homozygous LMNA variant

et al. 2019

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BackgroundDespite major advances in understanding the molecular basis of various genetic lipodystrophy syndromes, some rare patients still remain unexplained.CasesWe report a novel autosomal recessive lipodystrophy affecting two sisters aged 17 and 19 years and characterised by early onset intellectual disability, and subsequent development of near-generalised loss of subcutaneous fat with diabetes mellitus, extreme hypertriglyceridemia, hepatic steatosis, short stature, clinodactyly, joint contractures, leiomyoma of uterus and cataracts in childhood. The lipodystrophy was more pronounced in the upper and lower extremities, and there was no associated muscular hypertrophy. Using whole exome sequencing in this consanguineous Hispanic pedigree, we report disease-causing homozygous p.Arg545His LMNA variant in the affected subjects, and confirm the lack of pathogenic variants in other known lipodystrophy genes. The mother and a younger brother were both heterozygous for p.Arg545His LMNA variant and were overweight with acanthosis nigricans without any evidence of lipodystrophy. Our patients are distinct from previously reported autosomal recessive lipodystrophy syndromes and have no overlap with other autosomal recessive laminopathies, including mandibuloacral dysplasia, Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth neuropathy.ConclusionOur report of this unusual familial generalised lipodystrophy syndrome adds to the pleiotropy associated with biallelic autosomal recessive LMNA variants.

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Section: Discussionmentioning

confidence: 99%

A novel autosomal recessive lipodystrophy syndrome due to homozygous LMNA variant

et al. 2019

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“…Indeed, a recent study based on the analysis of variant frequencies in several public databases gathering data on 60, 706 unrelated individuals, revealed an unexpected high number of LMNA variants (n = 132), including novel variants predicted to perturb lamin A assembly or function. Among them, the variant p.Gly602Ser was identified as a potential risk factor for type 2 diabetes mellitus in African Americans [22].…”

Section: Discussionmentioning

confidence: 99%

Unraveling LMNA Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls

Desgrouas

Varlet

Dutour

et al. 2020

Cells

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This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in LMNA, c.1745G>T p.(Arg582Leu), and c.1892G>A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. In these two patients, subcutaneous adipose tissue was persistent, at least on the abdomen, and the serum leptin level remained in the normal range. Cellular studies showed elevated nuclear anomalies, an accelerated senescence rate and a decrease of replication capacity in patient cells. In cellular models, the overexpression of mutated prelamin A phenocopied misshapen nuclei, while the partial reduction of lamin A expression in patient cells significantly improved nuclear morphology. Altogether, these results suggest a link between lamin A mutant expression and senescence associated phenotypes. Transcriptome analysis of the whole subcutaneous adipose tissue from the two patients and three controls, paired for age and sex using RNA sequencing, showed the up regulation of genes implicated in immunity and the down regulation of genes involved in development and cell differentiation in patient adipose tissue. Therefore, our results suggest that some mutations in LMNA are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping.

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“…We found that progeria-associated deletions either abolished (Δ50) or greatly reduced (Δ35) lamin A modification by OGT in vitro. Interestingly, three missense variants that perturb metabolism are located in the ‘sweet spot’: p.G602S (insulin resistance syndrome [ 8 ]; type 2 diabetes [ 76 ]), p.G631D (metabolic syndrome; [ 12 ]), and p.R644C (multiple phenotypes; [ 77 ]). Variant p.L92F, identified in an obese patient with severe metabolic syndrome [ 13 ], adjoins the reported O -GlcNAc site at T91 [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

OGT (O-GlcNAc Transferase) Selectively Modifies Multiple Residues Unique to Lamin A

Simon

Wriston

Fan

et al. 2018

Cells

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The LMNA gene encodes lamins A and C with key roles in nuclear structure, signaling, gene regulation, and genome integrity. Mutations in LMNA cause over 12 diseases (‘laminopathies’). Lamins A and C are identical for their first 566 residues. However, they form separate filaments in vivo, with apparently distinct roles. We report that lamin A is β-O-linked N-acetylglucosamine-(O-GlcNAc)-modified in human hepatoma (Huh7) cells and in mouse liver. In vitro assays with purified O-GlcNAc transferase (OGT) enzyme showed robust O-GlcNAcylation of recombinant mature lamin A tails (residues 385–646), with no detectable modification of lamin B1, lamin C, or ‘progerin’ (Δ50) tails. Using mass spectrometry, we identified 11 O-GlcNAc sites in a ‘sweet spot’ unique to lamin A, with up to seven sugars per peptide. Most sites were unpredicted by current algorithms. Double-mutant (S612A/T643A) lamin A tails were still robustly O-GlcNAc-modified at seven sites. By contrast, O-GlcNAcylation was undetectable on tails bearing deletion Δ50, which causes Hutchinson–Gilford progeria syndrome, and greatly reduced by deletion Δ35. We conclude that residues deleted in progeria are required for substrate recognition and/or modification by OGT in vitro. Interestingly, deletion Δ35, which does not remove the majority of identified O-GlcNAc sites, does remove potential OGT-association motifs (lamin A residues 622–625 and 639–645) homologous to that in mouse Tet1. These biochemical results are significant because they identify a novel molecular pathway that may profoundly influence lamin A function. The hypothesis that lamin A is selectively regulated by OGT warrants future testing in vivo, along with two predictions: genetic variants may contribute to disease by perturbing OGT-dependent regulation, and nutrient or other stresses might cause OGT to misregulate wildtype lamin A.

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LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

Cited by 16 publications

References 97 publications

A novel autosomal recessive lipodystrophy syndrome due to homozygous LMNA variant

A novel autosomal recessive lipodystrophy syndrome due to homozygous LMNA variant

Unraveling LMNA Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls

OGT (O-GlcNAc Transferase) Selectively Modifies Multiple Residues Unique to Lamin A

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