Identification of Two Novel DNAAF2 Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia

Lu, Chenyang; Yang, Danhui; Cheng, Lei; Wang, Rongchun; Guo, Tao; Luo, Hong

doi:10.2147/pgpm.s338981

Cited by 8 publications

(9 citation statements)

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“…In addition, both patients had the classic PCD phenotype as well as the more commonly overlooked scoliosis. Although scoliosis is currently reported less commonly in patients with PCD, this phenotype is more frequently observed in model organisms carrying the causative gene for PCD, including CCDC40 , DNAAF4 , ODAD3 , and ZMYND10 ( Grimes et al, 2016 ; Kobayashi et al, 2017 ; Lu et al, 2021 ). A previous study evaluated chest radiographs in 198 patients with PCD and found a Cobb angle >10° in 8% of patients, but that study did not perform genetic analysis ( Schlösser et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, scoliosis is often overlooked in patients with PCD as anteroposterior and lateral radiographs of the spine are not a routine examination. Although there are few reports linking scoliosis to PCD, some genes have been reported to be associated with abnormal cilia beating and scoliosis in previous research (Fei et al, 2010;Makrythanasis et al, 2014;Baschal et al, 2015;Zhou et al, 2015;Lu et al, 2021;Nita et al, 2021). As an increasing number of PCD model organisms are observed with scoliosis, the spinal examination of the patient needs to be taken seriously.…”

Section: Discussionmentioning

confidence: 99%

“…To date, there have been no diagnostic tests that could be completely relied upon to confirm this disease ( Shapiro et al, 2016 ). About 50 genes have been reported as causative for PCD, of which those reported to be associated with asthenoteratozoospermia (reduced sperm motility and abnormal sperm morphology) and scoliosis are even rarer ( Coutton et al, 2015 ; Aprea et al, 2021 ; Lu et al, 2021 ). Asthenoteratozoospermia is an important cause of male infertility, which affects approximately 7% of the male population.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, scoliosis is another PCD-related phenotype reported in this article, which was defined as a spinal malformation in a patient who has skeletal maturation with a Cobb angle in the coronal plane >10° ( Aebi, 2005 ). Scoliosis can be observed in mice with some PCD causative gene variants, but it requires more attention in patients with PCD ( Baschal et al, 2015 ; Gao et al, 2015 ; Zhou et al, 2015 ; Lu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families

Guo

Yang

et al. 2022

Front. Genet.

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Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder, predominantly autosomal recessive. The dynein axonemal assembly factor 4 (DNAAF4) is mainly involved in the preassembly of multisubunit dynein protein, which is fundamental to the proper functioning of cilia and flagella. There are few reports of PCD-related pathogenic variants of DNAAF4, and almost no DNAAF4-related articles focused on sperm phenotype. Moreover, the association between DNAAF4 and scoliosis has never been reported, to the best of our knowledge.Materials and Methods: We recruited two patients with a clinical diagnosis of PCD. One came from a consanguineous and another from a non-consanguineous family. Clinical data, laboratory test results, and imaging data were analyzed. Through whole exome sequencing, immunofluorescence, electron microscopy, high-speed video microscopy analysis, and hematoxylin–eosin (HE) staining, we identified the disease-associated variants and validated the pathogenicity.Results: Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a non-consanguineous family-I, and proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-II. Both had sinusitis, bronchiectasis, situs inversus, and scoliosis. P1 also had asthenoteratozoospermia, and P2 had an immature uterus. Two homozygous pathogenic variants in DNAAF4 (NM_130810.4), c.988C > T, p.(Arg330Trp), and DNAAF4 (NM_130810.4), c.733 C > T, p.(Arg245*), were identified through whole exome sequencing. High-speed microscopy analysis showed that most of the cilia were static in P1, with complete static of the respiratory cilia in P2. Immunofluorescence showed that the outer dynein arms (ODA) and inner dynein arms (IDA) were absent in the respiratory cilia of both probands, as well as in the sperm flagellum of P1. Transmission electron microscopy revealed the absence of ODA and IDA of respiratory cilia of P2, and HE staining showed irregular, short, absent, coiled, and bent flagella.Conclusion: Our study identified a novel variant c.733C > T, which expanded the spectrum of DNAAF4 variants. Furthermore, we linked DNAAF4 to asthenoteratozoospermia and likely scoliosis in patients with PCD. This study will contribute to a better understanding of PCD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families

Guo

Yang

et al. 2022

Front. Genet.

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“…However, this pathology is not clearly associated with body axis maintenance. WES studies from two women of consanguineous families with PCD revealed that the mutation of the dynein axonemal assembly factor 2 (DNAAF2) gene may also be associated with spine malformation ( Lu et al, 2021 ). Both patients exhibited bronchiectasis, sinusitis and infertility, classical disorders in PCD, and one of them also presented situs inversus and scoliosis.…”

Section: Emerging Roles Of Genetic Factors Related To Scoliosis Devel...mentioning

confidence: 99%

Turning the Curve Into Straight: Phenogenetics of the Spine Morphology and Coordinate Maintenance in the Zebrafish

Muñoz-Montecinos

Romero

Sepúlveda

et al. 2022

Front. Cell Dev. Biol.

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The vertebral column, or spine, provides mechanical support and determines body axis posture and motion. The most common malformation altering spine morphology and function is adolescent idiopathic scoliosis (AIS), a three-dimensional spinal deformity that affects approximately 4% of the population worldwide. Due to AIS genetic heterogenicity and the lack of suitable animal models for its study, the etiology of this condition remains unclear, thus limiting treatment options. We here review current advances in zebrafish phenogenetics concerning AIS-like models and highlight the recently discovered biological processes leading to spine malformations. First, we focus on gene functions and phenotypes controlling critical aspects of postembryonic aspects that prime in spine architecture development and straightening. Second, we summarize how primary cilia assembly and biomechanical stimulus transduction, cerebrospinal fluid components and flow driven by motile cilia have been implicated in the pathogenesis of AIS-like phenotypes. Third, we highlight the inflammatory responses associated with scoliosis. We finally discuss recent innovations and methodologies for morphometrically characterize and analyze the zebrafish spine. Ongoing phenotyping projects are expected to identify novel and unprecedented postembryonic gene functions controlling spine morphology and mutant models of AIS. Importantly, imaging and gene editing technologies are allowing deep phenotyping studies in the zebrafish, opening new experimental paradigms in the morphometric and three-dimensional assessment of spinal malformations. In the future, fully elucidating the phenogenetic underpinnings of AIS etiology in zebrafish and humans will undoubtedly lead to innovative pharmacological treatments against spinal deformities.

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ADGB variants cause asthenozoospermia and male infertility

Zhang

et al. 2023

Hum Genet

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Identification of Two Novel DNAAF2 Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia

Cited by 8 publications

References 40 publications

Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families

Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families

Turning the Curve Into Straight: Phenogenetics of the Spine Morphology and Coordinate Maintenance in the Zebrafish

ADGB variants cause asthenozoospermia and male infertility

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