Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome

Luo, Minna; Lin, Zaisheng; Zhu, Tao; Jin, Minjun; Meng, Dan; He, Ruida; Cao, Zhen; Shen, Yue; Lü, Chao; Cai, Ruikun; Zhao, Yong; Wang, Xueyan; Li, Hui; Wu, Shijing; Zou, Xuan; Luo, Guanjun; Cao, Li; Huang, Min; Jiao, Huike; Gao, Huafang; Sui, Ruifang; Zhao, Chengtian; Ma, Xu; Cao, Muqing

doi:10.1038/s41436-021-01106-z

Cited by 28 publications

(30 citation statements)

References 40 publications

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“…The pleiotropicity of these ciliopathies may be caused by the variety of IFT74 mutations. For instance, we found that the BBS variant of IFT74 (∆561-600-IFT74) lost its binding ability with IFT27, which is a Small GTPase-like protein required for BBSome function [33,34], while the JBTS variant (p. Q179E) maintains its binding activity with IFT27 [20]. It is apparent that the IFT74 variants reported in humans are hypomorphic, while our zebrafish mutants are likely to be a null allele, causing ciliogenesis defects in almost every organ.…”

Section: Discussionmentioning

confidence: 73%

“…In humans, IFT74 deficiency has been implicated in several ciliopathies, including BBS and JBTS [20][21][22]. Recently, male sterility due to impaired flagellogenesis was also reported [30].…”

Section: Discussionmentioning

confidence: 99%

“…To knockdown the expression of the ift74 gene, we used a morpholino targeting to the 5 untranslated region (ATG-MO) and an anti-splice site morpholino (SP-MO). These morpholinos were the same as described previously [20] (Table S1).…”

Section: Morpholino Knockdownmentioning

confidence: 99%

“…The interaction between IFT74 and IFT81 proteins forms a module that is essential for the binding of tubulin, the backbone, and the most abundant ciliary proteins [19]. Recently, IFT74 has been identified as causative for human ciliopathies, Bardet-Biedl syndrome (BBS), and Joubert syndrome (JBTS) [20][21][22]. The role of IFT74 during embryonic development remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Loss of Ift74 Leads to Slow Photoreceptor Degeneration and Ciliogenesis Defects in Zebrafish

Zhu

Wang

et al. 2021

IJMS

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Cilia are microtubule-based structures projecting from the cell surface that perform diverse biological functions. Ciliary defects can cause a wide range of genetic disorders known collectively as ciliopathies. Intraflagellar transport (IFT) proteins are essential for the assembly and maintenance of cilia by transporting proteins along the axoneme. Here, we report a lack of Ift74, a core IFT-B protein, leading to ciliogenesis defects in multiple organs during early zebrafish development. Unlike rapid photoreceptor cell death in other ift-b mutants, the photoreceptors of ift74 mutants exhibited a slow degeneration process. Further experiments demonstrated that the connecting cilia of ift74 mutants were initially formed but failed to maintain, which resulted in slow opsin transport efficiency and eventually led to photoreceptor cell death. We also showed that the large amount of maternal ift74 transcripts deposited in zebrafish eggs account for the main reason of slow photoreceptor degeneration in the mutants. Together, our data suggested Ift74 is critical for ciliogenesis and that Ift proteins play variable roles in different types of cilia during early zebrafish development. To our knowledge, this is the first study to show ift-b mutant that displays slow photoreceptor degeneration in zebrafish.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Morpholino Knockdownmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of Ift74 Leads to Slow Photoreceptor Degeneration and Ciliogenesis Defects in Zebrafish

Zhu

Wang

et al. 2021

IJMS

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“…In this case report, we describe a third patient with BBS due to a biallelic pathogenic variant predicted to affect splicing in IFT74 . Pathogenic variants in IFT74 also have recently been described in patients along the ciliopathy spectrum, including those with abnormal sperm motility 17 and Joubert syndrome 18 …”

Section: Introductionmentioning

confidence: 99%

Third case of Bardet‐Biedl syndrome caused by a biallelic variant predicted to affect splicing of IFT74

et al. 2021

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Bardet‐Biedl syndrome (BBS) is a rare ciliopathy characterized by rod‐cone dystrophy, postaxial polydactyly, truncal obesity and renal anomalies with autosomal recessive inheritance. We describe a 6‐year‐old male with early onset retinal dystrophy, postaxial polydactyly, truncal obesity and motor delays. Exome sequencing revealed a homozygous variant predicted to affect splicing of the IFT74 gene, c.1685‐1G > T. This is the third patient with BBS due to variants predicting loss of function in IFT74. All three patients have had retinal dystrophy, polydactyly, obesity, developmental differences, and a notable lack of renal anomalies. We recommend that IFT74 is added to gene panels for the diagnosis of BBS.

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Genotype–phenotype correlates in Joubert syndrome: A review

Gana

Serpieri

Valente

2022

American J of Med Genetics Pt C

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Joubert syndrome (JS) is a genetically heterogeneous primary ciliopathy characterized by a pathognomonic cerebellar and brainstem malformation, the “molar tooth sign,” and variable organ involvement. Over 40 causative genes have been identified to date, explaining up to 94% of cases. To date, gene‐phenotype correlates have been delineated only for a handful of genes, directly translating into improved counseling and clinical care. For instance, JS individuals harboring pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis, while pathogenic variants in NPHP1, RPGRIP1L, and TMEM237 are frequently associated to JS with renal involvement, requiring a closer monitoring of liver parameters, or renal functioning. On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease. These examples highlight how an accurate description of the range of clinical symptoms associated with defects in each causative gene, including the rare ones, would better address prognosis and help guiding a personalized management. This review proposes to address this issue by assessing the available literature, to confirm known, as well as to propose rare gene‐phenotype correlates in JS.

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Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome

Cited by 28 publications

References 40 publications

Loss of Ift74 Leads to Slow Photoreceptor Degeneration and Ciliogenesis Defects in Zebrafish

Loss of Ift74 Leads to Slow Photoreceptor Degeneration and Ciliogenesis Defects in Zebrafish

Third case of Bardet‐Biedl syndrome caused by a biallelic variant predicted to affect splicing of IFT74

Genotype–phenotype correlates in Joubert syndrome: A review

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