Leu124Serfs*26, a novel AGPAT2 mutation in congenital generalized lipodystrophy with early cardiovascular complications

Abstract

Background: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by the near-total loss of subcutaneous adipose tissue soon after birth, resulting in ectopic fat deposition and severe metabolic disturbances. Most cases are caused by AGPAT2 or BSCL2 gene mutations. We aimed to report two unrelated CGL patients with a novel frameshift mutation in AGPAT2 (p.Leu124Serfs*26). Methods: Clinical features and laboratory were obtained by medical interview and medical records review. DNA was extracted, amplified and sequenced. Mutation Taster was used to estimate the potential biological impact of the AGPAT2 mutations on the protein function. Results: Patient 1: a 30-year-old woman with lipodystrophy phenotype at birth and diagnosis of diabetes at age 13 presented with severe hypertriglyceridemia and pancreatitis at age 17, hypertension and albuminuria at age 18, proliferative diabetic retinopathy with visual loss at age 25, and an acute myocardial infarction due to multivessel coronary disease during a hospitalization for forefoot amputation at age 29. At this time, she required hemodialysis due to endstage renal disease. Patient 2: a 12-year-old girl with lipodystrophy phenotype and hypertriglyceridemia detected in the first year of life and abnormalities in the global longitudinal strain, evaluated by speckle-tracking echocardiography last year. Molecular analysis identified a c.369_372delGCTC (p.Leu124Serfs*26) AGPAT2 mutation in both unrelated patients, a compound heterozygous mutation in Patient 1, and homozygous mutation in Patient 2. Conclusion: We describe two unrelated patients with type 1 CGL due to Leu124Serfs*26, a novel AGPAT2 frameshift mutation, presenting as early cardiovascular disease. These findings suggest an association between Leu124Serfs*26 and a more aggressive phenotype.

Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

“…Pathways include metabolism [ [89], CTSD (cathepsin D) [90], ACADS (acyl-CoA dehydrogenase short chain) [91], IRF7 [92], S1PR1 [93], ZAP70 [94], IDH1 [95], IL15 [96], PIK3R1 [97], OSM (oncostatin M) [98], SOCS3 [99], USP21 [100], CEP19 [101], KDM2A [102], TP53 [103], BRD2 [104], ATP6 [105], BRD4 [106], COX2 [107], RPS6 [108], ND2 [109], CYTB (cytochrome b) [110] and COX1 [111] are altered expressed in obesity. Altered expression of BCL3 [112], TRAF2 [113], NEU1 [114], SNAP29 [115], AGPAT2 [116], LPCAT3 [117], ADORA2B [118], CTSD (cathepsin D) [119], ACADS (acyl-CoA dehydrogenase short chain) [120], ACAD9 [121], E4F1 [122], IRF7 [123], TAF1 [124], S1PR1 [125], RASSF1 [126], ELAC2 [127], RNF146 [128], COX15 [129], SMYD2 [130], IDH1 [131], MTO1 [132], IL15 [133], PIK3R1 [134], ASB1 [135], OSM (oncostatin M)…”

Coronary arterial calcification in patients with congenital generalised lipodystrophy: A case series

“…It is characterised by a loss of subcutaneous adipose tissue and marked insulin resistance, with consequences including diabetes, hypertriglyceridemia, hepatic steatosis, polycystic ovary syndrome, acanthosis nigricans , and arterial hypertension 2 . Early myocardial revascularization and cases of multivessel coronary disease leading to acute myocardial infarction in a young patient (29 years) have been described 3 . We have previously described infections, liver complications, and cardiovascular disease (CVD) as causes of death in CGL patients 4 .…”

“…2 Early myocardial revascularization and cases of multivessel coronary disease leading to acute myocardial infarction in a young patient (29 years) have been described. 3 We have previously described infections, liver complications, and cardiovascular disease (CVD) as causes of death in CGL patients. 4 Deaths from CVD have been reported in patients between 20 and 62 years of age, and necropsy studies have reported stiffness of intramural coronary arteries with intimal fibrosis and subendocardial collagen deposition.…”

Case report: A novel mutation of RecQ-like helicase 5 in a Chinese family with early myocardial infarction, coronary artery disease, and stroke hemiplegia

“…Recent studies have shown that some lipid metabolism genes, such as cholesteryl ester transfer protein (CETP) and ATP-binding cassette subfamily A member 1 (ABCA1) may indirectly cause MI by affecting coronary atherosclerosis progression ( Li et al, 2021 ; Wang et al, 2022 ). Simultaneously, mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2), autophagy-related 16-like 1 (ATG16L1), and RecQ-like helicase 5 (RECQL5) have been reported to possibly lead to MI in patients ( Xie et al, 2016 ; Montenegro Junior et al, 2020 ; Han et al, 2021 ). In addition, some correlation studies imply that polymorphisms in energy metabolism-related genes such as mitochondrially encoded tRNA leucine 1 (MT-TL1) and isocitrate dehydrogenase (NADP(+)) 2 (IDH2) may be associated with the onset of MI ( Cosma et al, 2022 ; Watany et al, 2022 ).…”