Absence of CEP78 causes photoreceptor and sperm flagella impairments in mice and a human individual

Zhu, Tianyu; Zhang, Yuxin; Sheng, Xunlun; Zhang, Xiangzheng; Chen, Yu; Zhu, Huang; Guo, Yueshuai; Qi, Yaling; Zhao, Yichen; Qi, Zhang; Chen, Xue; Guo, Xuejiang; Zhao, Chunxia

doi:10.7554/elife.76157

Cited by 5 publications

(2 citation statements)

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“…5 To date, variants of nearly 40 genes have been identified and related to approximately 60%-70% of patients with MMAF, including the genes of cilia-and flagella-associated proteins (CFAPs; e.g., CFAP43, CFAP44, CFAP47, CFAP57, CFAP58, CFAP61, CFAP65, CFAP69, CFAP70, CFAP74, CFAP91, and CFAP251), the genes of dynein axonemal heavy chain family (DNAHs; e.g., DNAH1, DNAH2, DNAH6, DNAH8, DNAH10, and DNAH17), and other genes expressed in sperm axonemal and peri-axonemal structures (DZIP1, CEP78, CEP128, CEP135, AKAP3, AKAP4, TTC21A, TTC29, ARMC2, AK7, FSIP2, QRICH2, SPEF2, ODF2). 4,[6][7][8] The DNAH1 gene, which is located at chromosome 3p21.1 with a length of approximately 84.17 kb and encodes a predicted 4625-amino acid protein, had been firstly described of gene-disease relationship with the MMAF phenotype. 9 It is highly expressed in the brain, testis, and respiratory tract, with an eightfold higher level in the testis than in the trachea.…”

Section: Introductionmentioning

confidence: 99%

“…Multiple morphological abnormalities of sperm flagella (MMAF) is a special type of asthenoteratozoospermia mainly caused by genetic factors, characterized by absent, short, coiled, angulation, and irregular‐caliber flagella 5 . To date, variants of nearly 40 genes have been identified and related to approximately 60%–70% of patients with MMAF, including the genes of cilia‐ and flagella‐associated proteins (CFAPs; e.g., CFAP43 , CFAP44 , CFAP47 , CFAP57 , CFAP58 , CFAP61 , CFAP65 , CFAP69 , CFAP70 , CFAP74 , CFAP91 , and CFAP251 ), the genes of dynein axonemal heavy chain family (DNAHs; e.g., DNAH1 , DNAH2 , DNAH6 , DNAH8 , DNAH10 , and DNAH17 ), and other genes expressed in sperm axonemal and peri‐axonemal structures ( DZIP1 , CEP78 , CEP128 , CEP135 , AKAP3 , AKAP4 , TTC21A , TTC29 , ARMC2 , AK7 , FSIP2 , QRICH2 , SPEF2 , ODF2 ) 4,6–8 …”

Section: Introductionmentioning

confidence: 99%

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Novel biallelic variants in DNAH1 cause multiple morphological abnormalities of sperm flagella with favorable outcomes of fertility after ICSI in Han Chinese males

Long

et al. 2023

Andrology

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BackgroundMultiple morphological abnormalities of sperm flagella is an idiopathic asthenoteratozoospermia characterized by absent, short, coiled, angulation, and irregular‐caliber flagella. Genetic variants of DNAH1 gene have been identified as a causative factor of multiple morphological abnormalities of sperm flagella and intracytoplasmic sperm injection is an available strategy for infertile males with dynein axonemal heavy chain 1 defects to conceive.ObjectivesTo identify novel variants and candidate mutant hotspots of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans.Materials and methodsThe DNAH1 variants were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning and transmission electron microscopy, and immunostaining were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic DNAH1 variants.ResultsWe identified 18 different DNAH1 variants in 11 unrelated families, including nine missense variants (p.A2564T, p.T3657R, p.G1862R, p.L2296P, p.T4041I, p.L611P, p.A913D, p.R1932Q, p.R2356W) and nine loss‐of‐function variants (c.2301‐1G>T, p.Q1518*, p.R1702*, p.D2845Mfs*2, p.P3909Rfs*33, p.Q4040Dfs*33, p.Q4058*, p.E4060Pfs*61, p.V4071Cfs*54). A total of 66.7% (12/18) of the identified variants were novel. Morphological analysis based on Papanicolaou staining and scanning electron microscopy demonstrated the typical multiple morphological abnormalities of sperm flagella characteristics of dynein axonemal heavy chain 1‐deficient spermatozoa. Immunostaining further revealed the absence of inner dynein arms but not outer dynein arms, which induced a general ultrastructural disorganization, such as the loss of central pair and mis‐localization of the microtubule doublets and outer dense fibers. To date, seven affected couples have accepted the intracytoplasmic sperm injection treatment, and three of them have given birth to five healthy babies.Discussion and conclusionThese findings further expand the variant spectrum of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans, thus providing new information for the molecular diagnosis of asthenoteratozoospermia. The favorable fertility outcomes of intracytoplasmic sperm injection will facilitate the genetic counseling and clinical treatment of infertile males with multiple morphological abnormalities of sperm flagella in the future.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel biallelic variants in DNAH1 cause multiple morphological abnormalities of sperm flagella with favorable outcomes of fertility after ICSI in Han Chinese males

Long

et al. 2023

Andrology

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Exploring the diverse clinical and variant spectrum of CEP78‐associated syndrome: Novel pathogenic variants identified in a case series

Zhai,

Ballios

2024

American J of Med Genetics Pt A

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Dual sensory impairment, commonly referred to as combined hearing and vision loss, can stem from a diverse spectrum of conditions, each presenting with its unique set of clinical characteristics. Our understanding of dual sensory impairment has expanded significantly in the past decade, broadening the scope of genetic differential diagnoses, including genes such as CEP250, ARSG, TUBB4B, CEP78, and ABHD12. A case series including three patients from two families with genetically diagnosed CEP78‐associated cone–rod dystrophy was identified. We collected and reviewed their clinical records, imaging data, and genetic testing results. In addition, a comprehensive literature review was conducted on the phenotype and the genetic testing modality employed in all published CEP78 cases through a PubMed search using the keyword “CEP78.” A retinal dystrophy panel detected a novel homozygous CEP78 pathogenic variant (c.1447C>T, p.Arg483*) in siblings—Cases 1 and 2—from Family 1. Both teenagers have a clinical diagnosis of cone–rod dystrophy with presumed normal hearing. Case 3 from Family 2, diagnosed with cone–rod dystrophy and early‐onset hearing loss, was found to carry a CEP78 pathogenic variant (c.1206‐2A>C) and a likely pathogenic variant (c.856_857del, p.Leu286Glyfs*12) also through panel‐based genetic testing. Intriguingly, neither of these variants was reported in an affected sibling's clinical whole‐exome sequencing (WES) report when performed in 2015. A review of CEP78‐related literature unveiled that the initial report linking CEP78 to cone–rod dystrophy and hearing loss was published in September 2016. Any pathogenic variant found in CEP78 before 2016 would have been categorized as a “clearly disruptive variant in a gene of uncertain significance (GUS)” and might not have been reported in the WES report. It is important to acknowledge that our understanding of genotype–phenotype associations is undergoing rapid expansion. It is also crucial to recognize that repeat genetic testing may represent a fundamentally different approach, given the technological advancements not only in the coverage of the sequencing but also in the more comprehensive understanding of genotype–phenotype associations. This case series also enriches the existing CEP78 literature by providing phenotypic details of the youngest case of CEP78‐associated retinopathy reported in the literature (Case 2), which expands our perspective on the natural history of disease in this disorder.

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STYXL1 regulates CCT complex assembly and flagellar tubulin folding in sperm formation

Chen,

Luo,

et al. 2024

Nat Commun

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Tubulin-based microtubule is a core component of flagella axoneme and essential for sperm motility and male fertility. Structural components of the axoneme have been well explored. However, how tubulin folding is regulated in sperm flagella formation is still largely unknown. Here, we report a germ cell-specific co-factor of CCT complex, STYXL1. Deletion of Styxl1 results in male infertility and microtubule defects of sperm flagella. Proteomic analysis of Styxl1-/- sperm reveals abnormal downregulation of flagella-related proteins including tubulins. The N-terminal rhodanese-like domain of STYXL1 is important for its interactions with CCT complex subunits, CCT1, CCT6 and CCT7. Styxl1 deletion leads to defects in CCT complex assembly and tubulin polymerization. Collectively, our findings reveal the vital roles of germ cell-specific STYXL1 in CCT-facilitated tubulin folding and sperm flagella development.

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Absence of CEP78 causes photoreceptor and sperm flagella impairments in mice and a human individual

Cited by 5 publications

References 44 publications

Novel biallelic variants in DNAH1 cause multiple morphological abnormalities of sperm flagella with favorable outcomes of fertility after ICSI in Han Chinese males

Novel biallelic variants in DNAH1 cause multiple morphological abnormalities of sperm flagella with favorable outcomes of fertility after ICSI in Han Chinese males

Exploring the diverse clinical and variant spectrum of CEP78‐associated syndrome: Novel pathogenic variants identified in a case series

STYXL1 regulates CCT complex assembly and flagellar tubulin folding in sperm formation

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