A human laterality disorder associated with recessive<i>CCDC11</i>mutation

Perles, Zeev; Cinnamon, Yuval; Ta‐Shma, Asaf; Shaag, Avraham; Einbinder, Tom; Rein, Azaria J.J.T.; Elpeleg, Orly

doi:10.1136/jmedgenet-2011-100457

Cited by 51 publications

(51 citation statements)

References 38 publications

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“…There is a growing body of evidence that these two laterality disorders, SIT and heterotaxia, are part of a phenotypic continuum, with the same genetic defects underlying them. This phenotypic variability was described by us in individuals with mutations in CCDC11 and WDR16 38 and by others in patients harbouring deleterious changes in ZIC3 39. We also tested mmp21 suppression or mutation in zebrafish.…”

Section: Discussionmentioning

confidence: 69%

A human laterality disorder caused by a homozygous deleterious mutation inMMP21

et al. 2015

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Background Laterality in the vertebrate embryo is determined by left–right asymmetric gene expression driven by the flow of extraembryonic fluid across the embryonic node. Defects in these processes cause heterotaxy, the abnormal formation and arrangement of visceral organs that can range from complete inversion of symmetry to the selective misarrangement of organs. However, our understanding of the genetic causality for laterality defects in human beings remains relatively limited. Methods We performed whole exome sequencing in a consanguineous family with heterotaxia. To interrogate the pathogenic potential of the discovered variant, we used an in vivo system in which the potential of the candidate gene to induce L-R asymmetry was tested by transient suppression and CRISPR/Cas9-induced deletions. We also used in vitro assays to test a possible link between our exome-derived candidate and Notch signaling. Results We identified a homozygous 2 bp deletion in MMP21, encoding matrix metalloproteinase-21, as the sole coding mutation that segregated with the phenotype. Transient suppression or CRISPR/Cas9-mediated deletion of mmp21 in zebrafish embryos induced cardiac looping defects, with concomitant disruption of laterality markers in the lateral plate mesoderm and disrupted notch signalling in vitro and in vivo. Conclusions Our data implicate loss of MMP21 as a cause of heterotaxy in humans with concomitant defects in Notch signaling. In support of this finding, a homozygous missense mutation in MMP21 was identified previously in mice with N-Ethyl-N-Nitrosourea (ENU)-induced heterotaxy. Taken together, these observations suggest a role of matrix metalloproteinases in the establishment of asymmetric organ development, likely through the regulation of morphogenetic signals.

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Section: Discussionmentioning

confidence: 69%

A human laterality disorder caused by a homozygous deleterious mutation inMMP21

et al. 2015

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“…Recently, an association between CCDC11 and disorder of LR asymmetry has been reported [Perles et al., ]. The affected individual analyzed in that study is homozygous for a splice site mutation which does not completely disrupt the CCDC11 protein.…”

Section: Discussionmentioning

confidence: 87%

Mutations in CCDC11 , which Encodes a Coiled-Coil Containing Ciliary Protein, Causes Situs Inversus Due to Dysmotility of Monocilia in the Left-Right Organizer

et al. 2015

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In vertebrates, establishment of left-right (LR) asymmetry is dependent on cilia-driven fluid flow within the LR organizer. Mutations in CCDC11 disrupt LR asymmetry in humans, but how the gene functions in LR patterning is presently unknown. We describe a patient with situs inversus totalis carrying homozygous loss-of-function mutations in CCDC11. We show that CCDC11 is an axonemal protein in respiratory cilia, but is largely dispensable for their structure and motility. To investigate the role of CCDC11 in LR development, we studied the zebrafish homolog of the gene. Like in human respiratory cilia, loss of Ccdc11 causes minor defects in the motility of zebrafish kidney cilia, although the protein localizes to their axonemes and base. By contrast, Ccdc11 localizes exclusively to the basal bodies of cilia within Kupffer's vesicle, the organ of laterality of teleost fishes, and within the spinal canal. Moreover, the rotational motion of the cilia in these tissues of ccdc11-deficient embryos was strongly impaired. Our findings demonstrate that CCDC11 has a conserved essential function in cilia of the vertebrate LR organizer. To the best of our knowledge, this is the first ciliary component, which has a differential localization and function in different kinds of motile cilia.

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“…Pathogenic mechanisms of SIT have not been well elucidated. Some genetic patterns are involved including an autosomal recessive gene located to chromosome 14 [9] and deletions affecting chromosomes 7 or 8 [10]; Recently, significant advancements in understanding the possible molecular pathways were made suggesting that mutation affecting CCDC11 and DNAH11 genes are involved in autosomal recessive laterality defects of diverse phenotype resulting in SIT [11,12]. In addition, it has been shown that mutations in the TGF- β family gene and in the transcription factor HNF-3 β have a probable role in the process [13].…”

Section: Discussionmentioning

confidence: 99%

Common bile duct adenocarcinoma in a patient with situs inversus totalis: report of a rare case

et al. 2012

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BackgroundSitus inversus totalis represents an unusual anomaly characterized by a mirror-image transposition of the abdominal and thoracic viscera. It often occurs concomitantly with other disorders that make difficult diagnosis and management of abdominal pathology. The relationship between situs inversus totalis and cancer remains unclear.Case presentationWe describe a 33-year old Guinean man with situs inversus totalis who presented with obstructive jaundice. Imaging and endoscopic modalities demonstrated a mass of distal common bile duct which biopsy identified an adenocarcinoma. The patient was successfully treated by cephalic pancreaticoduodenectomy followed by adjuvant chemoradiation and he is doing well without recurrence 8 months after surgery.ConclusionThe occurrence of bile duct adenocarcinoma in patient with situs inversus totalis accounts as a rare coincidence. In this setting, when the tumor is resectable, surgical management should be considered without contraindication and must be preceded by a careful preoperative staging.

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A human laterality disorder associated with recessiveCCDC11mutation

Cited by 51 publications

References 38 publications

A human laterality disorder caused by a homozygous deleterious mutation inMMP21

A human laterality disorder caused by a homozygous deleterious mutation inMMP21

Mutations in CCDC11 , which Encodes a Coiled-Coil Containing Ciliary Protein, Causes Situs Inversus Due to Dysmotility of Monocilia in the Left-Right Organizer

Common bile duct adenocarcinoma in a patient with situs inversus totalis: report of a rare case

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