DCDC2 Mutations Cause a Renal-Hepatic Ciliopathy by Disrupting Wnt Signaling

Schueler, Markus; Braun, Daniela A.; Chandrasekar, Gayathri; Gee, Heon Yung; Klasson, Timothy D.; Halbritter, Jan; Bieder, Andrea; Porath, Jonathan D.; Airik, Rannar; Zhou, Weibin; LoTurco, Joseph J.; Che, Alicia; Otto, Edgar A.; Böckenhauer, Detlef; Sebire, Neil J.; Honzík, Tomáš; Harris, Peter C.; Koon, Sarah; Gunay‐Aygun, Meral; Saunier, Sophie; Zerres, Klaus; Bruechle, Nadina Ortiz; Drenth, Joost P.H.; Pelletier, Laurence; Tapia-Páez, Isabel; Lifton, Richard P.; Giles, Rachel; Kere, Juha; Hildebrandt, Friedhelm

doi:10.1016/j.ajhg.2014.12.002

Cited by 101 publications

(120 citation statements)

References 40 publications

(60 reference statements)

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“…Strikingly, a second dyslexia candidate gene, DCDC2, was found to be essential to ciliary function following discovery of a homozygous missense variant cosegregating with congenital deafness in a consanguineous family (53). Expression of the deafness-associated variant in rat inner ear organotypic cultures, and gene knockdown in zebrafish, confirmed the ciliary role (53,141). Renal-hepatic ciliopathy was subsequently found to result from homozygous or compound heterozygous DCDC2 variants that likely abolish protein production through nonsense-mediated mRNA decay (141).…”

Section: Can Birdsong Inform the Neurogenetics Of Language?mentioning

confidence: 61%

“…Renal-hepatic ciliopathy was subsequently found to result from homozygous or compound heterozygous DCDC2 variants that likely abolish protein production through nonsense-mediated mRNA decay (141). Reexamination of Dcdc2-deficient mice revealed periportal liver fibrosis, like that observed in patients with DCDC2 loss-of-function variants (141).…”

Section: Can Birdsong Inform the Neurogenetics Of Language?mentioning

confidence: 97%

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Understanding Language from a Genomic Perspective

Graham

Fisher

2015

Annu. Rev. Genet.

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Language is a defining characteristic of the human species, but its foundations remain mysterious. Heritable disorders offer a gateway into biological underpinnings, as illustrated by the discovery that FOXP2 disruptions cause a rare form of speech and language impairment. The genetic architecture underlying language-related disorders is complex, and although some progress has been made, it has proved challenging to pinpoint additional relevant genes with confidence. Next-generation sequencing and genome-wide association studies are revolutionizing understanding of the genetic bases of other neurodevelopmental disorders, like autism and schizophrenia, and providing fundamental insights into the molecular networks crucial for typical brain development. We discuss how a similar genomic perspective, brought to the investigation of language-related phenotypes, promises to yield equally informative discoveries. Moreover, we outline how follow-up studies of genetic findings using cellular systems and animal models can help to elucidate the biological mechanisms involved in the development of brain circuits supporting language.

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Section: Can Birdsong Inform the Neurogenetics Of Language?mentioning

confidence: 61%

Section: Can Birdsong Inform the Neurogenetics Of Language?mentioning

confidence: 97%

Understanding Language from a Genomic Perspective

Graham

Fisher

2015

Annu. Rev. Genet.

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“…In humans and mouse 11 paralogs in the DCX -repeat gene family have been described [16]. Dcdc2 knockout mice exhibit multiply disrupted development in memory capacity and phonological processing as well as bile duct proliferation and liver fibrosis [17, 18]. …”

Section: Discussionmentioning

confidence: 99%

“…How loss of ciliary integrity predisposes to inflammation and cholestasis, with the phenotype of neonatalonset cholangiopathy, is at present unclear [21]. We suggest that the absence of DCDC2 may be implicated either in the formation of “cytotoxic” bile or in dysregulation of the cholangiocyte’s homeostatic mechanisms, perhaps via Wnt signalling [17]. …”

Section: Discussionmentioning

confidence: 99%

Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis

Grammatikopoulos

Sambrotta

Strautnieks

et al. 2016

Journal of Hepatology

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Background & Aims Neonatal sclerosing cholangitis (NSC) is a severe neonatal-onset cholangiopathy commonly leading to liver transplantation (LT) for end-stage liver disease in childhood. Liver-biopsy findings histopathologically resemble those in biliary atresia (BA); however, in NSC extrahepatic bile ducts are patent, whilst in BA their lumina are obliterated. NSC is commonly seen in consanguineous kindreds, suggesting autosomal recessive inheritance. Methods From 29 NSC patients (24 families) identified, DNA was available in 24 (21 families). Thirteen (7 male) patients (12 families) of consanguineous parentage were selected for whole exome sequencing. Sequence variants were filtered for homozygosity, pathogenicity, minor allele frequency, quality score, and encoded-protein expression pattern. Results Four of 13 patients were homozygous and two were compound heterozygous for mutations in DCDC2, encoding doublecortin domain containing 2 (DCDC2), expressed in cholangiocyte cilia. Another 11 patients were sequenced: one (with one sibling pair) was compound heterozygous for DCDC2 mutations. All mutations were protein-truncating. In available liver tissue from patients with DCDC2 mutations, immunostaining for human DCDC2 and the ciliary protein acetylated alpha-tubulin (ACALT) showed no expression (n=6) and transmission electron microscopy found that cholangiocytes lacked primary cilia (n=5). DCDC2 and ACALT were expressed in NSC patients without DCDC2 mutations (n=22). Of the DCDC2, one patient died awaiting LT; five came to LT, of whom one died 2 years later. The other 4 are well. Conclusion Among 24 NSC patients with available DNA, 7 had mutations in DCDC2 (6 of 19 families). NSC patients in substantial proportion harbour mutations in DCDC2. Their disease represents a novel liver-based ciliopathy.

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“…For family 2 ( Figure 1A), we collected blood samples and pedigree information from the affected individual (2-II-4) and his mother after obtaining informed consent and analyzed them as previously described. 7,8 Approval for human subject research was obtained from the institutional review boards of Tel HaShomer Hospital and Boston Children's Hospital. We captured genomic DNA with an Agilent SureSelect All Exome Kit v.2.0 (Agilent Technologies) and sequenced the library on a HiSeq instrument (Illumina) to obtain a mean target coverage of 453 (Table S1).…”

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confidence: 99%

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

Ta‐Shma

Khan

Vivante

et al. 2017

The American Journal of Human Genetics

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Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.Whole-exome and whole-genome sequencing (WES and WGS, respectively) have accelerated the expansion of the repertoire of human loci underscoring Mendelian phenotypes to account for~3,000 human genes (15%).1 Nonetheless, the diagnostic yield remains <50%, 2-4 suggesting that the majority of disease-causing lesions are yet to be identified and that a significant fraction of this genetic burden is likely to be contributed by ultra-rare or private mutations. To contribute to the saturation of the morbid human genome as a means of improving both diagnostic value and mechanistic insight, we undertook the systematic sequencing of families affected by suspected genetic disorders, with an emphasis on congenital syndromic traits. Here, we report the genetic and functional dissection of affected individuals with a genetically undiagnosed syndrome characterized by cardiac, CNS, renal, and digit abnormalities in two unrelated consanguineous pedigrees. We show that the likely molecular cause, homozygous truncating mutations in TMEM260, affect the functions of one of the two established isoforms transcribed from this locus, thereby demonstrating the necessity of the long isoform for the development of multiple tissues. We consulted family 1, a con...

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DCDC2 Mutations Cause a Renal-Hepatic Ciliopathy by Disrupting Wnt Signaling

Cited by 101 publications

References 40 publications

Understanding Language from a Genomic Perspective

Understanding Language from a Genomic Perspective

Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

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