Scholarlink

Background <p>Bardet-Biedl syndrome is a pleiotropic ciliopathy marked by retinal degeneration, obesity, polydactyly, renal and reproductive anomalies, and cognitive impairment. <i>BBS1</i>, the most frequently mutated gene in Bardet-Biedl syndrome, encodes a key component of the BBSome complex, which is essential for ciliary membrane trafficking. Although BBS1 is known to be essential for proper BBSome function, the effects of disease-associated BBS1 variants on its activity remain incompletely understood.</p> Methods <p>In this study, we examined how patient-derived BBS1 mutations affect BBSome integrity and its role in cargo transport within primary cilia.</p> Results <p>Our results show that particular BBS1 mutations interfere with distinct stages of BBSome assembly and trafficking. While M390R disrupts initial pre-BBSome assembly at pericentriolar satellites, E224K impairs both the maturation of the pre-BBSome into the BBSome and its movement from pericentriolar satellites to the cilium. In contrast, the R160Q variant preserves BBSome assembly and permits its localization to cilia. It specifically weakens the BBSome-GPCR interaction mediated by TOM1L2, resulting in defective GPR161 export and increased ciliary IFT turnover.</p> Conclusions <p>Overall, our study establishes a mechanistic framework linking specific BBS1 mutations to distinct defects in BBSome assembly and function. This framework defines functional classes of BBS1 variants and provides deeper insight into the molecular mechanism and severity of Bardet-Biedl syndrome.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Bardet-Biedl syndrome 1 mutations differentially impact BBSome integrity and ciliary trafficking

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月19日

查看全文
  • Kristyna Maskova,
  • Hana Hajsmanova,
  • Sofiia Bykova,
  • Sindija Smite,
  • Avishek Prasai,
  • Daniel Rozbesky,
  • Martina Huranova

摘要

Background

Bardet-Biedl syndrome is a pleiotropic ciliopathy marked by retinal degeneration, obesity, polydactyly, renal and reproductive anomalies, and cognitive impairment. BBS1, the most frequently mutated gene in Bardet-Biedl syndrome, encodes a key component of the BBSome complex, which is essential for ciliary membrane trafficking. Although BBS1 is known to be essential for proper BBSome function, the effects of disease-associated BBS1 variants on its activity remain incompletely understood.

Methods

In this study, we examined how patient-derived BBS1 mutations affect BBSome integrity and its role in cargo transport within primary cilia.

Results

Our results show that particular BBS1 mutations interfere with distinct stages of BBSome assembly and trafficking. While M390R disrupts initial pre-BBSome assembly at pericentriolar satellites, E224K impairs both the maturation of the pre-BBSome into the BBSome and its movement from pericentriolar satellites to the cilium. In contrast, the R160Q variant preserves BBSome assembly and permits its localization to cilia. It specifically weakens the BBSome-GPCR interaction mediated by TOM1L2, resulting in defective GPR161 export and increased ciliary IFT turnover.

Conclusions

Overall, our study establishes a mechanistic framework linking specific BBS1 mutations to distinct defects in BBSome assembly and function. This framework defines functional classes of BBS1 variants and provides deeper insight into the molecular mechanism and severity of Bardet-Biedl syndrome.