Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France.
Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, Brest, France.
Hum Mutat. 2021 Apr;42(4):385-391. doi: 10.1002/humu.24178. Epub 2021 Feb 19.
A gain-of-function missense variant in the CELA3B gene, p.Arg90Cys (c.268C>T), has recently been reported to cause pancreatitis in an extended pedigree. Herein, we sequenced the CELA3B gene in 644 genetically unexplained French chronic pancreatitis (CP) patients (all unrelated) and 566 controls. No obvious loss-of-function variants were identified. None of the six low-frequency or common missense variants detected showed significant association with CP. Nor did the aggregate rare/very rare missense variants (n = 14) show any significant association with CP. However, p.Arg90Leu (c.269G>T), which was found in four patients but no controls, and affects the same amino acid as p.Arg90Cys, serves to revert p.Arg90 to the human elastase ancestral allele. As p.Arg90Leu has previously been shown to exert a similar functional effect to that of p.Arg90Cys, our findings not only confirm the involvement of CELA3B in the etiology of CP but also pinpoint a new evolutionarily adaptive site in the human genome.
最近有报道称，CELA3B 基因中的一个功能获得性错义变异，p.Arg90Cys（c.268C>T），导致一个扩展家系的胰腺炎。在此，我们对 644 名遗传性未明的法国慢性胰腺炎（CP）患者（均无亲缘关系）和 566 名对照进行了 CELA3B 基因测序。未发现明显的功能丧失性变异。检测到的 6 个低频或常见的错义变异均与 CP 无显著关联。汇总的罕见/非常罕见的错义变异（n=14）也与 CP 无显著关联。然而，在四个患者中发现但在对照组中没有发现的 p.Arg90Leu（c.269G>T），与 p.Arg90Cys 影响相同的氨基酸，使 p.Arg90 回复到人类弹性蛋白酶的祖先等位基因。由于 p.Arg90Leu 先前已被证明具有与 p.Arg90Cys 相似的功能效应，我们的发现不仅证实了 CELA3B 参与 CP 的病因，而且还确定了人类基因组中一个新的进化适应性位点。
