New mutations in DYNC2H1 and WDR60 genes revealed by whole-exome sequencing in two unrelated Sardinian families with Jeune asphyxiating thoracic dystrophy

Cossu, Carla; Incani, Federica; Serra, Mauro; Coiana, Alessandra; Crisponi, Guido; Boccone, Loredana; Rosatelli, Maria Cristina

doi:10.1016/j.cca.2016.02.006

Cited by 19 publications

(29 citation statements)

References 67 publications

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“…Cytoplasmic dynein-1 includes the dynactin complex, which enables cytoplasmic dynein-1 to carry vesicular cargo, whereas the cytoplasmic dynein-2 complex includes two intermediate chains (WDR34, WDR60), one light intermediate chain (DYNC2LI1, also called D2LIC) and another light chain (TCTEX1D2) [75]. Mutations in the subunits of cytoplasmic dynein-2 that are not shared with cytoplasmic dynein-1 can cause ciliopathies: human mutations TCTEX1D2, WDR34 and WDR60 are associated with the same types of ciliopathies caused by mutations in the heavy chain, JATD and SRPS [76–80] It is likely that these components are also important for mammalian Hh signaling. Indeed, mutations in human DYNC2LI1 cause SRPS, and fibroblasts derived from patients with missense and nonsense mutations in DYNC2LI1 confirmed that alleles of the gene cause abnormal cilia morphology [76].…”

Section: Cytoplasmic Dynein-2: the Retrograde Ciliary Motormentioning

confidence: 99%

Microtubule Motors Drive Hedgehog Signaling in Primary Cilia

Agbu

Anderson

2017

Trends in Cell Biology

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The mammalian Hedgehog (Hh) signaling pathway is required for development and for maintenance of adult stem cells, and overactivation of the pathway can cause tumorigenesis. All responses to Hh family ligands in mammals require the primary cilium, an ancient microtubule-based organelle that extends from the cell surface. Genetic studies in mice and humans have defined specific functions for cilia-associated microtubule motor proteins: they act in the construction and disassembly of the primary cilium, they control cilia length and stability, and some have direct roles in mammalian Hh signal transduction. These studies highlight how integrated genetic and cell biological studies can define the molecular mechanisms that underlie cilia-associated health and disease.

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Section: Cytoplasmic Dynein-2: the Retrograde Ciliary Motormentioning

confidence: 99%

Microtubule Motors Drive Hedgehog Signaling in Primary Cilia

Agbu

Anderson

2017

Trends in Cell Biology

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“…These are recessively inherited developmental disorders characterized by short ribs, shortened tubular bones, polydactyly and multisystem organ defects ( Huber and Cormier-Daire, 2012 ). In recent years, whole exome-sequencing technology has enabled the identification of new mutations involved in skeletal ciliopathies, notably a range of mutations affecting DYNC2H1 (DHC2, [ Chen et al, 2016 ; Cossu et al, 2016 ; Dagoneau et al, 2009 ; El Hokayem et al, 2012 ; Mei et al, 2015 ; Merrill et al, 2009 ; Okamoto et al, 2015 ; Schmidts et al, 2013a ]). Additionally, mutations in WDR34 ( Huber et al, 2013 ; Schmidts et al, 2013b ), WDR60 ( Cossu et al, 2016 ; McInerney-Leo et al, 2013 ), LIC3/DYNC2LI1 ( Kessler et al, 2015 ; Taylor et al, 2015 ) and TCTEX1D2 ( Schmidts et al, 2015 ) have also been reported.…”

Section: Introductionmentioning

confidence: 99%

Dynein-2 intermediate chains play crucial but distinct roles in primary cilia formation and function

Vuolo

Stevenson

Heesom

et al. 2018

eLife

112

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The dynein-2 microtubule motor is the retrograde motor for intraflagellar transport. Mutations in dynein-2 components cause skeletal ciliopathies, notably Jeune syndrome. Dynein-2 contains a heterodimer of two non-identical intermediate chains, WDR34 and WDR60. Here, we use knockout cell lines to demonstrate that each intermediate chain has a distinct role in cilium function. Using quantitative proteomics, we show that WDR34 KO cells can assemble a dynein-2 motor complex that binds IFT proteins yet fails to extend an axoneme, indicating complex function is stalled. In contrast, WDR60 KO cells do extend axonemes but show reduced assembly of dynein-2 and binding to IFT proteins. Both proteins are required to maintain a functional transition zone and for efficient bidirectional intraflagellar transport. Our results indicate that the subunit asymmetry within the dynein-2 complex is matched with a functional asymmetry between the dynein-2 intermediate chains. Furthermore, this work reveals that loss of function of dynein-2 leads to defects in transition zone architecture, as well as intraflagellar transport.

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“…Therefore, we decided to proceed with a broad NGS ciliopathy panel approach targeting in total 345 genes known or hypothesized to cause ciliopathies. We were surprised to detect a homozygous truncating mutation in WDR60 , a gene only known hitherto to be mutated in patients with JATD and SRPS (Cossu et al, ; McInerney‐Leo et al, , ), diseases for which our patients do not show any evidence besides polydactyly.…”

Section: Discussionmentioning

confidence: 65%

“…WDR60 mutations identified in individuals with SRPS type III and JATD include nonsense (p.Gln631*), missense (p.Thr749Met, p.Gln947Leu) and truncating splice site (c.1703‐3T>A) variants (Cossu et al, ; McInerney‐Leo et al, , ). The mutation we describe (p.Ala15Glufs*90) is a frameshift mutation predicted to affect the N‐terminus of the protein.…”

Section: Discussionmentioning

confidence: 99%

“…Jeune asphyxiating thoracic dystrophy (JATD) and short‐rib polydactyly syndrome (SRPS) are severe skeletal dysplasia ciliopathies often leading to respiratory compromise and early death. They belong to the genetically heterogeneous group of short‐rib thoracic dystrophies and can be caused by biallelic mutations of WDR60 (Cossu et al, ; McInerney‐Leo et al, , ). Here, we describe a much milder ciliopathy phenotype caused by a homozygous truncating WDR60 mutation, thus broadening the phenotypic spectrum caused by WDR60 mutations and contributing to the clinical and mutational overlap in ciliopathies.…”

Section: Introductionmentioning

confidence: 99%

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Expanding the phenotype associated with biallelic WDR60 mutations: Siblings with retinal degeneration and polydactyly lacking other features of short rib thoracic dystrophies

Kakar

Horn²,

Decker³

et al. 2017

American J of Med Genetics Pt A

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Ciliopathies are disorders of the primary cilium that can affect almost all organs and that are characterized by pleiotropy and extensive intra- and interfamilial phenotypic variability. Accordingly, mutations in the same gene can cause different ciliopathy phenotypes of varying severity. WDR60 encodes a protein thought to play a role in the primary cilium's intraflagellar transport machinery. Mutations in this gene are a rare cause of Jeune asphyxiating thoracic dystrophy (JATD) and short-rib polydactyly syndrome (SRPS). Here we report on a milder and distinct phenotype in a consanguineous Pakistani pedigree with two adolescent sisters affected by retinal degeneration and postaxial polydactyly, but lack of any further skeletal or chondrodysplasia features. By targeted high-throughput sequencing of genes known or suspected to be involved in ciliogenesis, we detected a novel homozygous N-terminal truncating WDR60 mutation (c.44delC/p.Ala15Glufs*90) that co-segregated with the disease in the family. Our finding broadens the spectrum of WDR60-related phenotypes and shows the utility of broad multigene panels during the genetic work-up of patients with ciliopathies.

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New mutations in DYNC2H1 and WDR60 genes revealed by whole-exome sequencing in two unrelated Sardinian families with Jeune asphyxiating thoracic dystrophy

Cited by 19 publications

References 67 publications

Microtubule Motors Drive Hedgehog Signaling in Primary Cilia

Microtubule Motors Drive Hedgehog Signaling in Primary Cilia

Dynein-2 intermediate chains play crucial but distinct roles in primary cilia formation and function

Expanding the phenotype associated with biallelic WDR60 mutations: Siblings with retinal degeneration and polydactyly lacking other features of short rib thoracic dystrophies

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