Infertility in an adult cohort with primary ciliary dyskinesia: phenotype–gene association

Vanaken, Gert‐Jan; Bassinet, L.; Boon, Mieke; Mani, Rahma; Honoré, Isabelle; Papon, Jean‐François; Cuppens, Harry; Jaspers, Martine; Lorent, Natalie; Coste, A.; Escudier, Estelle; Amselem, Serge; Maître, Bernard; Legendre, M.; Christin-Maître, Sophie

doi:10.1183/13993003.00314-2017

Cited by 118 publications

(137 citation statements)

References 15 publications

(9 reference statements)

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“…Male infertility was determined, only in adults, by a spermiogram after obtaining patients' informed consent. By contrast, females were considered infertile after 3 years of failure in their attempts to become pregnant [3,13]. Immunodeficiency was considered by immunoglobulins, blood cell counting, and C3 and C4 complement determination.…”

Section: Study Population and Clinical Datamentioning

confidence: 99%

Understanding Primary Ciliary Dyskinesia: Experience From a Mediterranean Diagnostic Reference Centre

Armengot-Carceller

Reula

Mata‐Roig

et al. 2020

JCM

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Background: Due to the lack of a gold standard diagnostic test, reference centres with experienced personnel and costly procedures are needed for primary ciliary dyskinesia (PCD) diagnostics. Diagnostic flowcharts always start with clinical symptoms. Therefore, the aim of this work is to define differential clinical criteria so that only patients clinically compatible with PCD are referred to reference centres. Materials and methods: 18 variables from 476 Mediterranean patients with clinically suspicious PCD were collected. After analysing cilia function and ultrastructure, 89 individuals were diagnosed with PCD and 387 had a negative diagnosis. Simple logistic regression analysis, considering PCD as a dependent variable and the others as independent variables, was done. In order to define the variables that best explain PCD, a step-wise logistic regression model was defined. Aiming to classify individuals as PCD or PCD-like patients, based on variables included in the study, a classification and regression tree (CART) was designed. Results and conclusions: Simple logistic regression analysis shows statistically significant association between age at the beginning of their symptomatology, periodicity, fertility, situs inversus, recurrent otitis, atelectasis, bronchiectasis, chronic productive cough, rhinorrea, rhinusinusitis and recurrent pneumonias, and PCD. The step-wise logistic regression model selected situs inversus, atelectasis, rhinorrea, chronic productive cough, bronchiectasis, recurrent pneumonias, and otitis as PCD predictive variables (82% sensitivity, 88% specificity, and 0.92 Area Under the Curve (AUC)). A decision tree was designed in order to classify new individuals based on pansinusitis, situs inversus, periodicity, rhinorrea, bronchiectasis, and chronic wet cough.

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Section: Study Population and Clinical Datamentioning

confidence: 99%

Understanding Primary Ciliary Dyskinesia: Experience From a Mediterranean Diagnostic Reference Centre

Armengot-Carceller

Reula

Mata‐Roig

et al. 2020

JCM

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“…This ciliary dysfunction leads to a mucociliary clearance defect responsible for chronic upper and lower airway infections (i.e., bronchitis and rhinosinusitis), and laterality randomization with situs inversus in nearly 50% of cases (Lobo, Zariwala, & Noone, ). Male infertility and female hypofertility are also common (Vanaken et al, ). The diagnosis of PCD is challenging and cannot rely on clinical features only.…”

Section: Mutation Spectrum In the 34 Investigated Familiesmentioning

confidence: 99%

Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele

et al. 2019

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Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North‐African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi‐allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North‐African patients. This mutation is estimated to date back at least 1,400–1,750 years ago. The identification of this major allele allowed us to suggest a cost‐effective genetic diagnostic strategy in North‐African patients with PCD.

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“…15 Consequently, although the sperm phenotype of PCD-affected individuals is generally poorly investigated, many of the PCD-associated genes have been linked to male infertility. 16 Hence, mutations in genes, such as DNAH5, 12 DNAI1, 17 DNAI2 18 and DNAH9, 19 encoding ODA components were suggested to induce male infertility. Although motile cilia and sperm flagella definitely share a similar axonemal structure, those organelles might display some structural and/or protein content differences that could explain (1) why not all men with PCD have asthenozoospermia and (2), conversely, the existence of axonemal defects restricted to the sperm flagella.…”

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confidence: 99%

Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia

Whitfield

Thomas

Béquignon

et al. 2019

The American Journal of Human Genetics

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Motile cilia and sperm flagella share an evolutionarily conserved axonemal structure. Their structural and/or functional defects are associated with primary ciliary dyskinesia (PCD), a genetic disease characterized by chronic respiratory-tract infections and in which most males are infertile due to asthenozoospermia. Among the well-characterized axonemal protein complexes, the outer dynein arms (ODAs), through ATPase activity of their heavy chains (HCs), play a major role for cilia and flagella beating. However, the contribution of the different HCs (gÀtype: DNAH5 and DNAH8 and bÀtype: DNAH9, DNAH11, and DNAH17) in ODAs from both organelles is unknown. By analyzing five male individuals who consulted for isolated infertility and displayed a loss of ODAs in their sperm cells but not in their respiratory cells, we identified bi-allelic mutations in DNAH17. The isolated infertility phenotype prompted us to compare the protein composition of ODAs in the sperm and ciliary axonemes from control individuals. We show that DNAH17 and DNAH8, but not DNAH5, DNAH9, or DNAH11, colocalize with a-tubulin along the sperm axoneme, whereas the reverse picture is observed in respiratory cilia, thus explaining the phenotype restricted to sperm cells. We also demonstrate the loss of function associated with DNAH17 mutations in two unrelated individuals by performing immunoblot and immunofluorescence analyses on sperm cells; these analyses indicated the absence of DNAH17 and DNAH8, whereas DNAH2 and DNALI, two inner dynein arm components, were present. Overall, this study demonstrates that mutations in DNAH17 are responsible for isolated male infertility and provides information regarding ODA composition in human spermatozoa.

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Infertility in an adult cohort with primary ciliary dyskinesia: phenotype–gene association

Cited by 118 publications

References 15 publications

Understanding Primary Ciliary Dyskinesia: Experience From a Mediterranean Diagnostic Reference Centre

Understanding Primary Ciliary Dyskinesia: Experience From a Mediterranean Diagnostic Reference Centre

Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele

Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia

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