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Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.

ABSTRACT: WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH₂-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.

SUBMITTER: Accogli A

PROVIDER: S-EPMC10774338 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.

Accogli Andrea A Shakya Saurabh S Yang Taewoo T Insinna Christine C Kim Soo Yeon SY Bell David D Butov Kirill R KR Severino Mariasavina M Niceta Marcello M Scala Marcello M Lee Hyun Sik HS Yoo Taekyeong T Stauffer Jimmy J Zhao Huijie H Fiorillo Chiara C Pedemonte Marina M Diana Maria C MC Baldassari Simona S Zakharova Viktoria V Shcherbina Anna A Rodina Yulia Y Fagerberg Christina C Roos Laura Sønderberg LS Wierzba Jolanta J Dobosz Artur A Gerard Amanda A Potocki Lorraine L Rosenfeld Jill A JA Lalani Seema R SR Scott Tiana M TM Scott Daryl D Azamian Mahshid S MS Louie Raymond R Moore Hannah W HW Champaigne Neena L NL Hollingsworth Grace G Torella Annalaura A Nigro Vincenzo V Ploski Rafal R Salpietro Vincenzo V Zara Federico F Pizzi Simone S Chillemi Giovanni G Ognibene Marzia M Cooney Erin E Do Jenny J Linnemann Anders A Larsen Martin J MJ Specht Suzanne S Walters Kylie J KJ Choi Hee-Jung HJ Choi Murim M Tartaglia Marco M Youkharibache Phillippe P Chae Jong-Hee JH Capra Valeria V Park Sung-Gyoo SG Westlake Christopher J CJ

Nature communications 20240108 1

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculosk ...[more]

PMID: 38191484

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Project description:Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human and mice. We identified two families carrying a deletion encompassing IFT74 exon 2, the first coding exon, resulting in a protein lacking the first 40 amino acids and two individuals carrying biallelic splice site mutations. Homozygous exon 2 deletion cases presented a ciliary chondrodysplasia with narrow thorax and progressive growth retardation along with a mucociliary clearance disorder phenotype with severely shorted cilia. Splice site variants resulted in a lethal skeletal chondrodysplasia phenotype. In mice, removal of the first 40 amino acids likewise results in a motile cilia phenotype but with little effect on primary cilia structure. Mice carrying this allele are born alive but are growth restricted and developed hydrocephaly in the first month of life. In contrast, a strong, likely null, allele of Ift74 in mouse completely blocks ciliary assembly and causes severe heart defects and midgestational lethality. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia resulting from increased mechanical stress and repair needs could account for the motile cilia phenotype observed in human and mice.

Dataset Information

Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.

Publications

Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.

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