Université Lyon 1, F-69622 Lyon, France.
Atherosclerosis. 2009 Nov;207(1):150-6. doi: 10.1016/j.atherosclerosis.2009.04.021. Epub 2009 Apr 24.
To provide phenotypic and functional data in new patients with APOA5 mutations and to identify genetic and metabolic factors influencing their phenotypic expression.
By sequencing APOA5 gene in a cohort of 286 hyperchylomicronemic subjects, free of LPL or APOC2 mutations, we identified 4 unrelated carriers of the Q97X mutation (3 heterozygotes and 1 homozygote) and one heterozygote with a new L242P mutation. Postheparin LPL activity level was reduced by about 50% in Q97X heterozygotes and more than 90% in the Q97X homozygote, but was normal in the L242P patient after resolution of hyperchylomicronemia. Plasma apoAV was undetectable in the Q97X homozygote and in the normal range in the L242P and Q97X heterozygous carriers. In Western blot studies, the association of apoAV with plasma lipoproteins was altered in Q97X heterozygous carriers but not in the L242P carrier. Hyperchylomicronemic heterozygotes for both mutations carried an additional APOA5 variant haplotype and/or APOE variant (E2 or E4). Type 2 diabetes or metabolic syndrome were not a major phenotypic determinant.
The L242P mutation was present in a hyperchylomicronemic proband but its causal involvement remains to be established. The Q97X mutation was clearly involved in hyperchylomicronemia with evidence of concomitant altered intravascular lipolysis, and a complete apoAV deficiency in the homozygote. The phenotypic expression variability of APOA5 mutations was mostly influenced by compound heterozygosity with APOA5 variant haplotypes plus additional genetic factors, and in a lesser extent by the metabolic environment.
为新的 APOA5 突变患者提供表型和功能数据，并确定影响其表型表达的遗传和代谢因素。
通过对 286 名无 LPL 或 APOC2 突变的高乳糜微粒血症患者的 APOA5 基因进行测序，我们发现了 4 名 Q97X 突变的无关联携带者（3 名杂合子和 1 名纯合子）和 1 名 L242P 新突变的杂合子。Q97X 杂合子的肝素后 LPL 活性水平降低了约 50%，而 Q97X 纯合子的 LPL 活性水平降低了 90%以上，但在高乳糜微粒血症得到解决后，L242P 患者的 LPL 活性水平正常。Q97X 纯合子的血浆 apoAV 无法检测到，而 L242P 和 Q97X 杂合子携带者的 apoAV 处于正常范围内。在 Western blot 研究中，Q97X 杂合子携带者中 apoAV 与血浆脂蛋白的结合发生了改变，但 L242P 携带者中没有改变。这两种突变的高乳糜微粒血症杂合子携带了额外的 APOA5 变体单倍型和/或 APOE 变体（E2 或 E4）。2 型糖尿病或代谢综合征不是主要的表型决定因素。
L242P 突变存在于高乳糜微粒血症患者中，但因果关系仍有待确定。Q97X 突变显然与高乳糜微粒血症有关，证据表明同时伴有血管内脂肪分解的改变，纯合子中 apoAV 完全缺乏。APOA5 突变的表型表达变异性主要受 APOA5 变体单倍型加其他遗传因素的复合杂合性影响，在较小程度上受代谢环境的影响。
