From the Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), University of Palermo, Palermo, Italy (A.B.C., R.S., D.N., V.I., A. Giammanco, M.D.P., A. Ganci, C.M.B., M.R.A.); and Molecular Biology Diagnostic Laboratory, Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), AOUP "Paolo Giaccone", Palermo, Italy (A.B.C., R.S., D.N., V.V., V.I., M.R.A.).
Arterioscler Thromb Vasc Biol. 2015 Dec;35(12):2694-9. doi: 10.1161/ATVBAHA.115.306170. Epub 2015 Oct 1.
Cyclic AMP responsive element-binding protein 3-like 3 (CREB3L3) is a novel candidate gene for dominant hypertriglyceridemia. To date, only 4 kindred with dominant hypertriglyceridemia have been found to be carriers of 2 nonsense mutations in CREB3L3 gene (245fs and W46X). We investigated a family in which hypertriglyceridemia displayed an autosomal dominant pattern of inheritance.
The proband was a 49-year-old woman with high plasma triglycerides (≤1300 mg/dL; 14.68 mmol/L). Her father had a history of moderate hypertriglyceridemia, and her 51-year-old brother had triglycerides levels as high as 1600 mg/dL (18.06 mmol/L). To identify the causal mutation in this family, we analyzed the candidate genes of recessive and dominant forms of primary hypertriglyceridemia by direct sequencing. The sequencing of CREB3L3 gene led to the discovery of a novel minute frame shift mutation in exon 3 of CREB3L3 gene, predicted to result in the formation of a truncated protein devoid of function (c.359delG-p.K120fsX20). Heterozygosity for the c.359delG mutation resulted in a severe phenotype occurring later in life in the proband and her brother and a good response to diet and a hypotriglyceridemic treatment. The same mutation was detected in a 13-year-old daughter who to date is normotriglyceridemic.
We have identified a novel pathogenic mutation in CREB3L3 gene in a family with dominant hypertriglyceridemia with a variable pattern of penetrance.
环磷酸腺苷反应元件结合蛋白 3 样 3（CREB3L3）是一种新的候选基因，可导致显性高甘油三酯血症。迄今为止，仅发现 4 个家族的 CREB3L3 基因携带 2 个无义突变（245fs 和 W46X），为显性高甘油三酯血症的携带者。我们研究了一个家族，该家族的高甘油三酯血症呈常染色体显性遗传模式。
先证者是一名 49 岁的女性，血浆甘油三酯水平较高（≤1300mg/dL；14.68mmol/L）。其父亲有中度高甘油三酯血症病史，51 岁的哥哥甘油三酯水平高达 1600mg/dL（18.06mmol/L）。为了鉴定该家族的致病突变，我们通过直接测序分析了常染色体隐性和显性形式的原发性高甘油三酯血症的候选基因。对 CREB3L3 基因的测序导致发现了 CREB3L3 基因外显子 3 中的一个新的微小移框突变，该突变预测会导致形成一个无功能的截短蛋白（c.359delG-p.K120fsX20）。c.359delG 突变的杂合性导致先证者及其哥哥在生命后期出现严重表型，并对饮食和降甘油三酯治疗有良好的反应。在一名 13 岁的女儿中也检测到了相同的突变，迄今为止，她的甘油三酯水平正常。
我们在一个具有可变外显率的显性高甘油三酯血症家族中发现了 CREB3L3 基因的一个新的致病突变。
