Sperm defects in primary ciliary dyskinesia and related causes of male infertility

AbstractThe core axoneme structure of both the motile cilium and sperm tail has the same ultrastructural 9 + 2 microtubular arrangement. Thus, it can be expected that genetic defects in motile cilia also have an effect on sperm tail formation. However, recent studies in human patients, animal models and model organisms have indicated that there are differences in components of specific structures within the cilia and sperm tail axonemes. Primary ciliary dyskinesia (PCD) is a genetic disease with symptoms caused by malfunction of motile cilia such as chronic nasal discharge, ear, nose and chest infections and pulmonary disease (bronchiectasis). Half of the patients also have situs inversus and in many cases male infertility has been reported. PCD genes have a role in motile cilia biogenesis, structure and function. To date mutations in over 40 genes have been identified cause PCD, but the exact effect of these mutations on spermatogenesis is poorly understood. Furthermore, mutations in several additional axonemal genes have recently been identified to cause a sperm-specific phenotype, termed multiple morphological abnormalities of the sperm flagella (MMAF). In this review, we discuss the association of PCD genes and other axonemal genes with male infertility, drawing particular attention to possible differences between their functions in motile cilia and sperm tails.

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Rare Human Diseases: Model Organisms in Deciphering the Molecular Basis of Primary Ciliary Dyskinesia

Cells ◽

10.3390/cells8121614 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1614 ◽

Cited By ~ 1

Author(s):

Martyna Poprzeczko ◽

Marta Bicka ◽

Hanan Farahat ◽

Rafal Bazan ◽

Anna Osinka ◽

...

Keyword(s):

Molecular Basis ◽

Primary Ciliary Dyskinesia ◽

State Of The Art ◽

Model Organisms ◽

Phenotypic Changes ◽

Current State ◽

Evolutionarily Conserved ◽

Motile Cilia ◽

The Impact ◽

Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a recessive heterogeneous disorder of motile cilia, affecting one per 15,000–30,000 individuals; however, the frequency of this disorder is likely underestimated. Even though more than 40 genes are currently associated with PCD, in the case of approximately 30% of patients, the genetic cause of the manifested PCD symptoms remains unknown. Because motile cilia are highly evolutionarily conserved organelles at both the proteomic and ultrastructural levels, analyses in the unicellular and multicellular model organisms can help not only to identify new proteins essential for cilia motility (and thus identify new putative PCD-causative genes), but also to elucidate the function of the proteins encoded by known PCD-causative genes. Consequently, studies involving model organisms can help us to understand the molecular mechanism(s) behind the phenotypic changes observed in the motile cilia of PCD affected patients. Here, we summarize the current state of the art in the genetics and biology of PCD and emphasize the impact of the studies conducted using model organisms on existing knowledge.

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Bi-allelic BRWD1 variants cause male infertility with asthenoteratozoospermia and likely primary ciliary dyskinesia

Human Genetics ◽

10.1007/s00439-020-02241-4 ◽

2021 ◽

Author(s):

Ting Guo ◽

Chao-Feng Tu ◽

Dan-Hui Yang ◽

Shui-Zi Ding ◽

Cheng Lei ◽

...

Keyword(s):

Male Infertility ◽

Primary Ciliary Dyskinesia ◽

Ciliary Dyskinesia

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Unique among ciliopathies: primary ciliary dyskinesia, a motile cilia disorder

F1000Prime Reports ◽

10.12703/p7-36 ◽

2015 ◽

Vol 7 ◽

Cited By ~ 40

Author(s):

Kavita Praveen ◽

Erica E. Davis ◽

Nicholas Katsanis

Keyword(s):

Primary Ciliary Dyskinesia ◽

Motile Cilia ◽

Ciliary Dyskinesia

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Novel DNAAF6 variants identified by whole-exome sequencing cause male infertility and primary ciliary dyskinesia

Journal of Assisted Reproduction and Genetics ◽

10.1007/s10815-020-01735-4 ◽

2020 ◽

Vol 37 (4) ◽

pp. 811-820 ◽

Cited By ~ 1

Author(s):

Ying Wang ◽

Chaofeng Tu ◽

Hongchuan Nie ◽

Lanlan Meng ◽

Dongyan Li ◽

...

Keyword(s):

Male Infertility ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Primary Ciliary Dyskinesia ◽

Whole Exome ◽

Ciliary Dyskinesia

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Gene discovery for motile cilia disorders: mutation spectrum in primary ciliary dyskinesia and discovery of mutations in CCDC151

Cilia ◽

10.1186/2046-2530-4-s1-p30 ◽

2015 ◽

Vol 4 (Suppl 1) ◽

pp. P30

Author(s):

A Onoufriadis ◽

R Hjeij ◽

CM Watson ◽

CE Slagle ◽

NT Klena ◽

...

Keyword(s):

Primary Ciliary Dyskinesia ◽

Gene Discovery ◽

Mutation Spectrum ◽

Motile Cilia ◽

Ciliary Dyskinesia

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Mutations in C11ORF70 cause primary ciliary dyskinesia with randomization of left/right body asymmetry due to outer and inner dynein arm defects

10.1101/218206 ◽

2017 ◽

Author(s):

Inga M. Höben ◽

Rim Hjeij ◽

Heike Olbrich ◽

Gerard W. Dougherty ◽

Tabea Menchen ◽

...

Keyword(s):

Male Infertility ◽

Primary Ciliary Dyskinesia ◽

Genetic Defect ◽

Clinical Importance ◽

Airway Disease ◽

Cytoplasmic Dynein ◽

Loss Of Function ◽

Reading Frame ◽

Dynein Arms ◽

Ciliary Dyskinesia

AbstractPrimary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility and randomization of the left/right body axis caused by defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open reading frame C11ORF70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11ORF70 cause immotility of respiratory cilia and sperm flagella, respectively, due to loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11ORF70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11ORF70 showed that C11ORF70 is expressed in ciliated respiratory cells and that the expression of C11ORF70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein arm assembly factors. Furthermore, C11ORF70 shows an interaction with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11ORF70 is a novel preassembly factor involved in the pathogenesis of PCD. The identification of a novel genetic defect that causes PCD and male infertility is of great clinical importance as well as for genetic counselling.

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A novel hypomorphic allele of Spag17 causes primary ciliary dyskinesia phenotypes in mice

Disease Models & Mechanisms ◽

10.1242/dmm.045344 ◽

2020 ◽

Vol 13 (10) ◽

pp. dmm045344

Author(s):

Zakia Abdelhamed ◽

Marshall Lukacs ◽

Sandra Cindric ◽

Heymut Omran ◽

Rolf W. Stottmann

Keyword(s):

Cerebrospinal Fluid ◽

Fluid Flow ◽

Primary Ciliary Dyskinesia ◽

Human Condition ◽

Central Pair ◽

Cerebrospinal Fluid Flow ◽

Hypomorphic Allele ◽

Motile Cilia ◽

The Brain ◽

Ciliary Dyskinesia

ABSTRACTPrimary ciliary dyskinesia (PCD) is a human condition of dysfunctional motile cilia characterized by recurrent lung infection, infertility, organ laterality defects and partially penetrant hydrocephalus. We recovered a mouse mutant from a forward genetic screen that developed many of the hallmark phenotypes of PCD. Whole-exome sequencing identified this primary ciliary dyskinesia only (Pcdo) allele to be a nonsense mutation (c.5236A>T) in the Spag17 coding sequence creating a premature stop codon (K1746*). The Pcdo variant abolished several isoforms of SPAG17 in the Pcdo mutant testis but not in the brain. Our data indicate differential requirements for SPAG17 in different types of motile cilia. SPAG17 is essential for proper development of the sperm flagellum and is required for either development or stability of the C1 microtubule structure within the central pair apparatus of the respiratory motile cilia, but not the brain ependymal cilia. We identified changes in ependymal ciliary beating frequency, but these did not appear to alter lateral ventricle cerebrospinal fluid flow. Aqueductal stenosis resulted in significantly slower and abnormally directed cerebrospinal fluid flow, and we suggest that this is the root cause of the hydrocephalus. The Spag17Pcdo homozygous mutant mice are generally viable to adulthood but have a significantly shortened lifespan, with chronic morbidity. Our data indicate that the c.5236A>T Pcdo variant is a hypomorphic allele of Spag17 that causes phenotypes related to motile, but not primary, cilia. Spag17Pcdo is a useful new model for elucidating the molecular mechanisms underlying central pair PCD pathogenesis in the mouse.This article has an associated First Person interview with the first author of the paper.

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