ATP6V1B2基因突变所致疾病及发病机制

Diseases and pathogenesis of ATP6V1B2 gene mutations

ATP6V1B2(ATPase H+ transporting V1 subunit B2)基因突变可导致显性遗传性耳聋-甲发育不全(dominant deafness and onychodystrophy,DDOD,MIM124480)综合征和Zimmermann-Laband综合征2(ZLS2,MIM616455)。DDOD综合征的患者临床表现为先天性感音神经性耳聋和甲发育不良,最新研究表明患者还存在学习和认知问题。ZLS2综合征的患者表现为牙龈异常增生、甲发育不良和智力障碍,但是若突变位点偏向ATP6V1B2蛋白中心,则突出表现为智力障碍和癫痫,而没有明显的牙龈异常增生和甲发育不良。ATP6V1B2基因编码液泡型质子转运ATPase蛋白(vacuolar proton transporter ATPase,V-ATPase)V1结构域的中B2亚基,V-ATPase对维持细胞内和细胞器正常的酸碱环境至关重要。目前认为该基因的致病性变异所导致的V-ATPase功能障碍和溶酶体酸化异常可能是DDOD综合征和ZLS2发病的分子基础。对Atp6v1b2 c.1516C>T基因敲入小鼠的深入研究发现:Atp6v1b2Arg506X / Arg506X的小鼠存在明显认知障碍,海马CA1区受损可能是其病理基础。B2亚基和E亚基的相互作用减弱可能是V-ATPase功能障碍的潜在分子机制。深入分析比较ATP6V1B2基因致病突变所导致的疾病表型,并对致病突变进行功能研究有着重要的意义。

Mutations of ATP6V1B2(ATPase H+transporting V1 subunit B2)gene may cause dominant hereditary deafness and onychodystrophy(DDOD,MIM124480)syndrome and Zimmermann-Laband syndrome 2(ZLS2,MIM616455).It is demonstrated that patients with DDOD syndrome have learning or memory problems as well as congenital sensorineural hearing loss and nail aplasia or hypoplasia.ZLS2 is mainly characterized by gingival hypertrophy,hypo/aplastic nails and intellectual disability.Individuals are reported to have intellectual disability,epilepsy and milder ZLS2-type characteristics if they carry the variants clustering towards the middle of the ATP6V1B2 protein.ATP6V1B2 gene encodes B2 subunit of the multimeric vacuolar H+ATPase(V-ATPase),which is a proton pump responsible for controlling the intracellular and extracellular pH of cells and organelles.Research on Atp6v1b2 c.1516C>T knockin mice showed that homozygous mice displayed obvious cognitive defects and impaired hippocampal CA1 region.A weak interaction between the E and B2 subunits might be the molecular mechanism underlyingV-ATPases dysfunction.It is of great significance to analyze and compare the phenotype caused by pathogenic mutations of ATP6V1B2 gene and to carry out functional research.