LMNA gene mutation search in Polish patients: new features of the heterozygous Arg482Gln mutation phenotype

Abstract

Mutations of the LMNA gene have been shown to cause an autosomal dominant form of insulin resistance with familial partial lipodystrophy (PLD), frequently accompanied by diabetes. LMNA mutations are considered to be a rare cause of monogenic diabetes; however, they are probably sometimes misdiagnosed as type 2 diabetes (T2DM). We examined whether skin fold thickness measurements may be an effective screening procedure to select individuals with T2DM for molecular testing of the LMNA gene. We also aimed to search for mutations in diabetic patients with evident clinical features of lipodystrophy. Skin fold measurements were performed in 249 not pre-selected T2DM patients. The sum of two trunk skin fold measurements divided by the sum of two peripheral was obtained. Men with a skin fold ratio above 2.5 and women above 1.5 were selected for further molecular analysis of the LMNA gene by direct sequencing. We also examined eight patients presenting typical clinical features of lipodystrophy. We selected 16 patients with T2DM on the basis of skin fold measurements. LMNA gene sequencing in this group revealed no mutation that could be attributable to diabetic phenotype. However, in the group of subjects with apparent lipodystrophic phenotype, we identified one Arg482Gln mutation. This female, diagnosed with diabetes at the age of 51 years, was characterized by insulin resistance but, unlike previously reported LMNA Arg48Gln mutation carriers, she was not overweight. The patient also presented with chronic kidney disease and pulmonary fibrosis that could potentially be a part of the phenotype related to the identified LMNA mutation. We did not find the evidence that screening based on skin fold measurements alone could be an efficient approach to select T2DM patients for molecular testing of the LMNA gene; the presence of features typical for laminopathy seems to be required for such testing. A clinical picture related to the LMNA Arg482Gln mutation may be more diversified than it was previously considered and include low BMI and pulmonary fibrosis.

Podocytopathies associated with familial partial lipodystrophy due to LMNA variants: report of two cases

“…identified the same variant in a patient with partial lipodystrophy, diabetes mellitus, chronic renal disease, and pulmonary fibrosis. This patient was suspected of having sarcoidosis, but this diagnosis was not confirmed and renal biopsy was not performed ( 21 ). Owen and cols.…”

Renal complications of lipodystrophy: A closer look at the natural history of kidney disease

“…Owen et al [20] reported the first case of FPLD who developed mesangiocapillary glomerulonephritis type II without low circulating C3 levels. Later, several additional patients with FPLD and CKD were reported by different authors [6, 7]. Low levels of circulating C3 have been associated with CKD in patients with APL [3].…”