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Last update 08 May 2025

CCDC40

Last update 08 May 2025

Basic Info

Synonyms

CCDC40, CFAP172, CILD15

+ [6]

Introduction

Required for assembly of dynein regulatory complex (DRC) and inner dynein arm (IDA) complexes, which are responsible for ciliary beat regulation, thereby playing a central role in motility in cilia and flagella (PubMed:21131974). Probably acts together with CCDC39 to form a molecular ruler that determines the 96 nanometer (nm) repeat length and arrangements of components in cilia and flagella (By similarity). Not required for outer dynein arm complexes assembly. Required for axonemal recruitment of CCDC39 (PubMed:21131974).

Drugs associated with CCDC40

ETH-42

Target

CCDC40

Mechanism

CCDC40 modulators

Active Org.

ETHRIS GmbH

Originator Org.

ETHRIS GmbH

Active Indication

Ciliary Motility Disorders

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

WO2024009306

Patent Mining

Target

CCDC40

Mechanism-

Active Org.

Skip Therapeutics Ltd.

Originator Org.

Skip Therapeutics Ltd.

Active Indication

Rare Diseases

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CCDC40

100 Translational Medicine associated with CCDC40

0 Patents (Medical) associated with CCDC40

Literatures (Medical) associated with CCDC40

01 Apr 2025·Pediatric Pulmonology

Genotype‐Phenotype Correlation in a Group of Italian Patients With Primary Ciliary Dyskinesia

Article

Author: De Luca, Alessandro ; Nenna, Raffaella ; Goldoni, Marina ; Mancino, Enrica ; Petrarca, Laura ; Cimino, Giuseppe ; Masuelli, Laura ; Guida, Valentina ; Conti, Maria Giulia ; Midulla, Fabio ; Poli, Piercarlo ; Bernardini, Laura

ABSTRACTIntroductionPrimary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by abnormalities in the motile cilia. Diagnosis could be hard to make, but genetic analysis could be important for the diagnosis and for defining prognosis.Aim of the StudyTo evaluate the clinical, ultrastructural, and molecular characteristics of a cohort of PCD subjects.Materials and MethodsThe study cohort included PCD patients enrolled in two Italian centers. Clinical data were retrospectively collected consulting medical records. All patients underwent nasal brushing and peripheral blood sampling for ultrastructural analysis of motile cilia and genetic testing, respectively.ResultsA total of 39 patients with PCD were enrolled (median age 25.5 years, range 2.5–54.3 years). All patients showed common clinical features, which included SIT in 22/39 (56.4%), chronic rhinitis in 31/39 (79.5%), chronic sinusitis in 26/37 (66.7%), chronic cough in 32/39 (82.1%), and neonatal respiratory distress in 46.2% (18/39). The genetic defect was identified in 27/39 patients (69.2%), while a diagnostic ultrastructure was found in 27/35 (77.1%). Assessing genotype‐phenotype correlations, subjects with biallelic pathogenic variants in CCDC39 and CCDC40 genes had a significantly lower forced expiratory volume in the first second of exhalation value (p = 0.017) than subjects with pathogenic variants in DNAH5 or in other PCD‐related genes.ConclusionsOur study further highlights the high heterogeneity of ultrastructural defects and genetics characterizing patients with PCD, as well as providing additional evidence that patients with biallelic pathogenic variants in CCDC39 or CCDC40 display a worse clinical phenotype than patients with pathogenic variants in other PCD genes.

01 Apr 2025·The Spine Journal

Novel rare variation of CCDC40 plays a role in the development of idiopathic scoliosis possibly via dysfunction of cilia motility

Article

Author: Zhu, Zezhang ; Wu, Zhichong ; Dai, Zhicheng ; Qiu, Yong ; Xu, Leilei ; Feng, Zhenhua

BACKGROUND CONTEXTMotile cilia dysfunction was reported to lead to scoliosis-like phenotypes in zebrafish models. There is still a lack of population-based study supporting the role of cilia motility associated genes in the etiology of idiopathic scoliosis (IS).PURPOSETo investigate the molecular mechanism underlying the relationship between cilia motility associated genes and the development of adolescent idiopathic scoliosis (AIS).STUDY DESIGNPopulation-based genetic study.METHODSA cohort of 56 female AIS patients and 30 age-matched nonscoliotic controls were included for tissue expression analysis. 28 patients with lower CCDC40 expression were selected for the exon sequencing. The novel variation was replicated in an independent cohort of 1326 AIS patients and 954 healthy controls. Exogenous versions of WT or mutant human CCDC40 mRNAs were expressed in zebrafish and the phenotype of body axis curvature was observed.RESULTSCCDC40 was found significantly down-expressed in AIS patients as compared with the nonscoliotic controls. A novel coding variant rs185157579 (c.1459G>A) was found significantly associated with AIS, with the mutant allele A adding to the risk of AIS by 2.44 folds. Zebrafish embryo injected with CCDC40 mRNAs containing mutant c.1459G>A presented significantly higher incidence of scoliosis-like phenotype than the wild group.CONCLUSIONSThe mutation c.1459G>A in the exon 10 of CCDC40 may lead to body axis curvature of zebrafish by impacting mRNA expression. The underlying molecular mechanism is worthy of further investigation.CLINICAL SIGNIFICANCEOur findings shed a new light on the etiopathogenesis of AIS. The downstream signaling of CCDC40 may be candidate for potential drug targets to prevent the development of AIS. Moreover, the novel variation can be used as a genetic marker of polygenic risk score predicting the risk of AIS.

01 Mar 2025·Andrology

A novel homozygous LRRC6 mutation causes male infertility with asthenozoospermia and primary ciliary dyskinesia in humans

Article

Author: Lin, Tingting ; Yang, Jie ; Hu, Tingwenyi ; Wang, Hongmei ; Shi, Juanzi ; Huang, Guoning ; Wang, Tianwei ; Qiao, Sen ; Shi, Shengjia ; Long, Shunhua ; Tang, Xiangrong

AbstractBackgroundDysfunction of motile cilia, including respiratory cilia and sperm flagella, typically leads to primary ciliary dyskinesia and male infertility or low fertility in humans. Genetic defects of LRRC6 have been associated with primary ciliary dyskinesia and asthenozoospermia due to abnormal ultrastructure of ciliated axonemes.ObjectivesTo identify novel mutations of the LRRC6 gene related to multiple morphological abnormalities of the sperm flagella and male infertility and investigate the underlying molecular mechanisms involved.Materials and methodsThe LRRC6 mutations were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning, and transmission electron microscopy were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Further tandem mass tagging proteomics analyses were performed to explore the effect of mutations and confirmed by immunostaining and western blotting. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic LRRC6 mutations.ResultsIn this study, we identified a novel homozygous LRRC6 mutation in a consanguineous family, characterized by asthenozoospermia and primary ciliary dyskinesia. Further Semen parameter and morphology analysis demonstrate that the novel LRRC6 mutation leads to a significant reduction in sperm flagella length, a decrease in sperm progressive motility parameters, and abnormalities of sperm ultrastructure. Specifically, the absence of outer dynein arms and inner dynein arms, and incomplete mitochondrial sheath in the flagellar mid‐piece were observed by transmission electron microscopy. In addition, tandem mass tagging proteomics analysis revealed that spermatozoa obtained from patients harboring the LRRC6 mutation exhibited a significant decrease in the expression levels of proteins related to the assembly and function of dynein axonemal arms. Functional analysis revealed that this novel LRRC6 mutation disrupted the function of the leucine‐rich repeat containing 6 protein, which in turn affects the expression of the dynein arm proteins and leucine‐rich repeat containing 6‐interacting proteins CCDC40, SPAG1, and ZMYND10. Finally, we reported a successful pregnancy through assisted reproductive technology with intracytoplasmic sperm injection in the female partner of the proband.Discussion and conclusionThis study highlights the identification of a novel homozygous LRRC6 mutation in a consanguineous family and its impact on sperm progressive motility, morphology, and sperm kinetics parameters, which could facilitate the genetic diagnosis of asthenozoospermia and offer valuable perspectives for future genetic counseling endeavors.

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CCDC40

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