A novel missense mutation in<i>CCDC88C</i>activates the JNK pathway and causes a dominant form of spinocerebellar ataxia

Tsoi, Ho; Yu, A C-S; Chen, Zhefan S; Ng, Nelson K N; Chan, Anne; Yuen, Liz Y P; Abrigo, Jill; Tsang, Suk Ying; Tsui, Stephen Kwok‐Wing; Tong, Tony M F; Lo, Ivan F.M.; Lam, Stephen; Mok, Vincent; Wong, Ka Sing; Ngo, Jacky Chi Ki; Lau, Kwok‐Fai; Chan, Ting-Fung; Chan, Ho Yin

doi:10.1136/jmedgenet-2014-102333

Cited by 67 publications

(70 citation statements)

References 31 publications

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“…Consistent with this was the finding that a Xenopus paralogue of Daple (xDal) is pivotal for the movements of convergent extension during gastrulation . To date, the reported involvement of Daple in the development and progression of human diseases constitutes a missense mutation in the human Daple gene ( CCDC88C ) that activates JNK and causes spinocerebellar ataxia …”

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confidence: 70%

Role for Daple in non‐canonical Wnt signaling during gastric cancer invasion and metastasis

et al. 2015

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In gastric cancer, the non-canonical Wnt signaling pathway is activated by Wnt5a, which has a critical role in disease outcome. Previous studies have shown that Wnt5a mediates the expression of the extracellular matrix protein laminin c2 through Rac and JNK activation to promote gastric cancer progression. However, the mechanism of this regulatory pathway has not been completely addressed. The scaffold protein Dvl is a major component of the Wnt signaling pathway. Here, we show that Dvl-associating protein with a high frequency of leucine residues (Daple) mediates Wnt5a-induced laminin c2 expression. Immunohistochemical analysis showed marked expression of Daple in advanced clinical stages of gastric cancer, where it highly correlated with Wnt5a ⁄ b and laminin c2 expression, the depth of wall invasion, and the frequency of lymph node metastasis. In cultured cancer cells, Daple depletion led to the suppression of Wnt5a-induced Rac and JNK activation, laminin c2 expression, and cell migration and invasion. Accordingly, Daple depletion also suppressed liver metastasis in a mouse xenograft model of gastric cancer. These results suggest that the non-canonical Wnt signaling pathway contributes to gastric cancer progression at least in part via Daple, which provides a new therapeutic opportunity for the treatment of the disease. Significant progress has been made in the diagnosis and treatment of gastric cancer, leading to a decrease in the mortality rate of patients with the disease. Nonetheless, many cases with delayed diagnosis and metastasis are intractable, making gastric cancer the third leading cause of cancer deaths worldwide.(1) To date, multiple genes, proteins and signaling pathways have been found to be deregulated in gastric cancer.(2-5) However, the mechanisms underlying the tumorigenesis, heterogeneity and metastasis of gastric cancer are less well understood.Previous studies have demonstrated that Wnt signaling represents one of the deregulated pathways in gastric cancer.(6) Wnt signaling is essential for embryonic development and adult tissue homeostasis and is involved in cancer initiation and progression. It consists of two distinct branches that signal intracellularly: canonical and non-canonical pathways.(7-9) Activation of the canonical pathway induces b-catenin nuclear accumulation and Wnt target gene transcription.(10) Mutations in components of the canonical pathway, such as b-catenin, adenomatous polyposis coli and Axin genes, are involved in human cancer initiation. (11,12) The non-canonical pathway is independent of b-catenin; instead, members of the Rho family of small GTPases, including Rac and Rho, and JNK transmit the signals to promote cell motility. (13,14) Accordingly, aberrant activation of non-canonical pathway components has been implicated as well in invasion and metastasis in human malignancies. (15) High levels of Wnt5a, a ligand that utilizes the non-canonical pathway, have been reported to promote invasion in advanced gastric cancer. (16)(17)(18) Wnt5a has been shown to induc...

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confidence: 70%

Role for Daple in non‐canonical Wnt signaling during gastric cancer invasion and metastasis

et al. 2015

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“…All affected individuals in the family had adult-onset spinocerebellar ataxia (SCA) rather than congenital hydrocephalus (Tsoi et al, 2014). The SCA-associated CCDC88C mutation was a missense variant (p.R464H) in the coiled coil domain.…”

Section: | Discussionmentioning

confidence: 99%

“…However, there continue to be significant gaps in our knowledge of these genetic causes due to absence of systematic data, and the paucity of known genes associated with isolated hydrocephalus (i.e., excluding well-studied syndromes in which hydrocephalus is a feature, such as the dystroglycanopathies). In 2010, recessive mutations of the CCDC88C gene were first identified in a large consanguineous multiplex family, with only two additional families identified since (Drielsma et al, 2012; Ekici et al, 2010; Tsoi et al, 2014). Here, we report a family of two affected children with congenital hydrocephalus due to a novel homozygous mutation in the CCDC88C gene, and we further characterize the spectrum of CCDC88C -associated hydrocephalus.…”

Section: | Introductionmentioning

confidence: 99%

Bi‐allelic mutations of CCDC88C are a rare cause of severe congenital hydrocephalus

Ruggeri¹,

Timms

Cheng³

et al. 2018

American J of Med Genetics Pt A

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Congenital or infantile hydrocephalus is caused by genetic and non-genetic factors and is highly heterogeneous in etiology. In recent studies, a limited number of genetic causes of hydrocephalus have been identified. To date, recessive mutations in the CCDC88C gene have been identified as a cause of non-syndromic congenital hydrocephalus in three reported families. Here, we report the fourth known family with two affected individuals with congenital hydrocephalus due to a homozygous mutation in the CCDC88C gene identified by whole exome sequencing. Our two newly described children, as well as the previously published ones, all shared several features including severe infantile-onset hydrocephalus, mild to severe intellectual delay, varying degrees of motor delay, and infantile onset seizures. All identified homozygous mutations in CCDC88C abolish the PDZ binding site necessary for proper CCDC88C protein function in the Wnt signaling pathway. Our report further establishes CCDC88C as one of the few known recessive causes of severe prenatal-onset hydrocephalus. Recognition of this syndrome has important diagnostic and genetic implications for families identified in the future.

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“…Because of overlapping phenotypes in different hereditary spastic paraplegia (HSP) subtypes (Pensato et al 2014), diagnosis of SPG11 is often supplemented with evidence from molecular genetics testing. In particular, next-generation sequencing is gaining traction as a tool for assisting the diagnosis and treatment of neurological diseases (Tsoi et al 2014; Petrovski et al 2015; Yang et al 2015; Ye et al 2015). …”

Section: Case Presentationmentioning

confidence: 99%

Whole-genome sequencing of two probands with hereditary spastic paraplegia reveals novel splice-donor region variant and known pathogenic variant in SPG11

Chan

et al. 2016

Cold Spring Harb Mol Case Stud

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Hereditary spastic paraplegias (HSPs) are a group of heterogeneous neurodegenerative disorders, which are often presented with overlapping phenotypes such as progressive paraparesis and spasticity. To assist the diagnosis of HSP subtypes, next-generation sequencing is often used to provide supporting evidence. In this study, we report the case of two probands from the same family with HSP symptoms, including bilateral lower limb weakness, unsteady gait, cognitive decline, dysarthria, and slurring of speech since the age of 14. Subsequent whole-genome sequencing revealed that the patients are compound heterozygous for variants in the SPG11 gene, including the paternally inherited c.6856C>T (p.Arg2286*) variant and the novel maternally inherited c.2316+5G>A splice-donor region variant. Variants in SPG11 are the common cause of autosomal recessive spastic paraplegia type 11. According to the ClinVar database, there are already 101 reported pathogenic variants in SPG11 that are associated with HSPs. To our knowledge, this is the first report of SPG11 variants in our local population. The novel splice variant identified in this study enriches the catalog of SPG11 variants, potentially leading to better genetic diagnosis of HSPs.

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A novel missense mutation inCCDC88Cactivates the JNK pathway and causes a dominant form of spinocerebellar ataxia

Cited by 67 publications

References 31 publications

Role for Daple in non‐canonical Wnt signaling during gastric cancer invasion and metastasis

Role for Daple in non‐canonical Wnt signaling during gastric cancer invasion and metastasis

Bi‐allelic mutations of CCDC88C are a rare cause of severe congenital hydrocephalus

Whole-genome sequencing of two probands with hereditary spastic paraplegia reveals novel splice-donor region variant and known pathogenic variant in SPG11

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