Exome sequencing identifies novel mutations in C5orf42 in patients with Joubert syndrome with oral–facial–digital anomalies

Wentzensen, Ingrid M.; Johnston, Jennifer J.; Keppler‐Noreuil, Kim M.; Acrich, Karina; David, Karen L.; Johnson, Kisha; Graham, John M.; Sapp, Julie C.; Biesecker, Leslie G.

doi:10.1038/hgv.2015.45

Cited by 20 publications

(32 citation statements)

References 13 publications

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“…16 These phenotypes are known to be caused by dysfunction of LIS1. Although defects in cilia-mediated signaling pathways are thought to be the major cause of abnormal proliferation in ciliopathies, defects in cell cycle progression may also be involved in the pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Monoallelic mutations in BUBR1, a core spindle checkpoint component that is regulated by mitotic proteolysis, have been shown to promote tumorigenesis in multiple tissues. [14][15][16] In addition, OFD VI patients showing severe phenotypes and early death have truncated mutations in JBTS17. 11 Another kinetochore protein, CENP-F, has also been identified as a ciliary protein that localizes to the mother centriole and moves along the ciliary axoneme.…”

Section: Discussionmentioning

confidence: 99%

“…14-16 JBTS17 supports basal body localization of PCP proteins, which is required to recruit IFT-A peripheral proteins for ciliogenesis and ciliary function. 14,16 Here, we report that JBTS17 localizes to the kinetochore and regulates mitotic progression. 18 Some patients with JBTS17 mutations show atypical phenotypes of ciliopathies, making it difficult to determine their association with ciliary dysfunction.…”

mentioning

confidence: 94%

“…18 Some patients with JBTS17 mutations show atypical phenotypes of ciliopathies, making it difficult to determine their association with ciliary dysfunction. 14,16 Here, we report that JBTS17 localizes to the kinetochore and regulates mitotic progression. We show that levels of JBTS17 oscillate during the cell cycle through proteasomal degradation.…”

mentioning

confidence: 94%

“…JBTS17, also known as C5ORF42, is a ciliopathy protein mutated in Joubert syndrome (JS) and oral-facial-digital syndrome VI (OFD VI). [14][15][16] JBTS17 supports basal body localization of PCP proteins, which is required to recruit IFT-A peripheral proteins for ciliogenesis and ciliary function. 17 JBTS17 mutant mice display ciliopathy-associated phenotypes such as cystic kidney, polydactyly, and craniofacial anomalies.…”

mentioning

confidence: 98%

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Extraciliary roles of the ciliopathy protein JBTS17 in mitosis and neurogenesis

Hong

Joo

Park

et al. 2019

Annals of Neurology

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Objective: JBTS17 is a major gene mutated in ciliopathies such as Joubert syndrome and oral-facial-digital syndrome type VI. Most patients with loss of function mutations in JBTS17 exhibit cerebellar vermis hypoplasia and brainstem malformation. However, some patients with JBTS17 mutations show microcephaly and abnormal gyration. We examined potential roles of JBTS17 in neurogenesis to understand the pathological mechanism of JBTS17-related cortical abnormalities. Methods: We examined subcellular localization and cell-cycle-dependent expression of JBTS17 proteins using anti-JBTS17 antibodies and JBTS17 expression vectors. We also performed knockdown experiments to determined roles of JBTS17 in human cells, and demonstrated mitotic functions of JBTS17 using immunostaining and live imaging. We examined the involvement of JBTS17 in cortical neurogenesis using a mouse in utero electroporation technique. Results: We found that JBTS17 localizes to the kinetochore and the level of JBTS17 is regulated by cell-cycle-dependent proteolysis. Depletion of JBTS17 disrupts chromosome alignment and spindle pole orientation, resulting in mitotic delay. JBTS17 interacts with LIS1 and influences LIS1 localization. Depletion of Jbts17 in the developing mouse cortex interferes with the mitotic progression of neural progenitors and the migration of postmitotic neurons. Interpretation: LIS1 is implicated in lissencephaly, but altered dosage of LIS1 has been also associated with microcephaly syndromes. Our results suggest that JBTS17 contributes to mitotic progression by interacting with LIS1, and abnormal mitosis is an underlying mechanism of the microcephaly phenotype in JBTS17-related ciliopathies. We propose that understanding extraciliary roles of ciliopathy proteins is important to elucidate pathological mechanisms underlying diverse ciliopathy phenotypes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 94%

mentioning

confidence: 98%

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Extraciliary roles of the ciliopathy protein JBTS17 in mitosis and neurogenesis

Hong

Joo

Park

et al. 2019

Annals of Neurology

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Ciliopathies: Coloring outside of the lines

Strong

Liu

Mentch

et al. 2020

American J of Med Genetics Pt A

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Ciliopathy syndromes are a diverse spectrum of disease characterized by a combination of cystic kidney disease, hepatobiliary disease, retinopathy, skeletal dysplasia, developmental delay, and brain malformations. Though generally divided into distinct disease categories based on the pattern of system involvement, ciliopathy syndromes are known to display certain phenotypic overlap. We performed next‐generation sequencing panel testing, clinical exome sequencing, and research‐based exome sequencing reanalysis on patients with suspected ciliopathy syndromes with additional features. We identified biallelic pathogenic variants in BBS1 in a child with features of cranioectodermal dysplasia, and biallelic variants in BBS12 in a child with the clinical stigmata of Bardet‐Biedl syndrome, but also with anal atresia. We additionally identified biallelic pathogenic variants in WDR35 and DYNC2H1 in children with predominant liver disease and ductal plate malformation without skeletal dysplasia. Our study highlights the phenotypic and genetic diversity of ciliopathy syndromes, the importance of considering ciliopathy syndromes as a disease‐spectrum and screening for all associated complications in all patients, and describes exclusive extra‐skeletal manifestations in two classical skeletal dysplasia syndromes.

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Expanding the genetic landscape of oral‐facial‐digital syndrome with two novel genes

Strong

Simone

Krentz³

et al. 2021

American J of Med Genetics Pt A

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Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy-spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.Ciliopathy syndromes are rare Mendelian disorders caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates proper organ patterning and growth (Berbari et al., 2009;Fry et al., 2014). Oral-facial-digital syndromes (OFDS) represent a heterogenous group of ciliopathies, characterized by the core features of oral cavity malformations, such as tongue hamartomas, cleft palate, lobulated tongue, and hyperplastic frenula, craniofacial dysmorphisms such as down-slanted palpebral

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Exome sequencing identifies novel mutations in C5orf42 in patients with Joubert syndrome with oral–facial–digital anomalies

Cited by 20 publications

References 13 publications

Extraciliary roles of the ciliopathy protein JBTS17 in mitosis and neurogenesis

Extraciliary roles of the ciliopathy protein JBTS17 in mitosis and neurogenesis

Ciliopathies: Coloring outside of the lines

Expanding the genetic landscape of oral‐facial‐digital syndrome with two novel genes

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