Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice

Moye, Abigail R.; Bedoni, Nicola; Cunningham, Jessica G.; Sanzhaeva, Urikhan; Tucker, Eric S.; Mathers, Peter H.; Peter, Virginie G.; Quinodoz, Mathieu; Paris, Liliana P; Coutinho-Santos, Luísa; Camacho, Pedro; Purcell, Madeleine G.; Winkelmann, Abbie C.; Foster, James A.; Pugacheva, Elena N.; Rivolta, Carlo; Ramamurthy, Visvanathan

doi:10.1371/journal.pgen.1008315

Cited by 23 publications

(27 citation statements)

References 49 publications

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“…Patients were ascertained at the Instituto de Oftalmologia Dr. Gama Pinto in Lisbon, Portugal, and informed consent was obtained from all family members included in this study. Clinical and ophthalmological assessment was performed as previously described (Moye et al, 2019). Audiological examinations were provided to us by the patients.…”

Section: Methodsmentioning

confidence: 99%

New clinical and molecular evidence linking mutations in ARSG to Usher syndrome type IV

Peter

Quinodoz

Sadio³

et al. 2020

Human Mutation

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In murine and canine animal models, mutations in the Arylsulfatase G gene (ARSG) cause a particular lysosomal storage disorder characterized by neurological phenotypes. Recently, two variants in the same gene were found to be associated with an atypical form of Usher syndrome in humans, leading to visual and auditory impairment without the involvement of the central nervous system. In this study, we identified three novel pathogenic variants in ARSG, which segregated recessively with the disease in two families from Portugal. The probands were affected with retinitis pigmentosa and sensorineural hearing loss, generally with an onset of symptoms in their fourth decade of life. Functional experiments showed that these pathogenic variants abolish the sulfatase activity of the Arylsulfatase G enzyme and impede the appropriate lysosomal localization of the protein product, which appears to be retained in the endoplasmic reticulum. Our data enable to definitely confirm that different biallelic variants in ARSG cause a specific deaf‐blindness syndrome, by abolishing the activity of the enzyme it encodes.

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Section: Methodsmentioning

confidence: 99%

New clinical and molecular evidence linking mutations in ARSG to Usher syndrome type IV

Peter

Quinodoz

Sadio³

et al. 2020

Human Mutation

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“…The same was true for the two other studies, where the presence of false-positive heterozygous genotypes was combined with the relatively short size of ROHs and/or the presence of a limited number of identifiable genotypes. In addition, AutoMap enabled the detection of new variants in a number of genes that were already associated with Mendelian conditions [35][36][37] . In conclusion, AutoMap is a reliable tool that can predict ROHs with high specificity and sensitivity, in less than a minute, even from VCF files derived from noisy exome sequencing data.…”

Section: Resultsmentioning

confidence: 99%

AutoMap is a high performance homozygosity mapping tool using next-generation sequencing data

Quinodoz

Peter

Bedoni³

et al. 2021

Nat Commun

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Homozygosity mapping is a powerful method for identifying mutations in patients with recessive conditions, especially in consanguineous families or isolated populations. Historically, it has been used in conjunction with genotypes from highly polymorphic markers, such as DNA microsatellites or common SNPs. Traditional software performs rather poorly with data from Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS), which are now extensively used in medical genetics. We develop AutoMap, a tool that is both web-based or downloadable, to allow performing homozygosity mapping directly on VCF (Variant Call Format) calls from WES or WGS projects. Following a training step on WES data from 26 consanguineous families and a validation procedure on a matched cohort, our method shows higher overall performances when compared with eight existing tools. Most importantly, when tested on real cases with negative molecular diagnosis from an internal set, AutoMap detects three gene-disease and multiple variant-disease associations that were previously unrecognized, projecting clear benefits for both molecular diagnosis and research activities in medical genetics.

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“…Subsequent GO analysis showed that these genes were mainly enriched in BP category including spermatogenesis, multicellular organism development, cell differentiation, spermatid development, and sperm motility, as well as in CC category including motile cilium, microtubule, acrosomal vesicle and nucleus. These are also the hotspots of research on male infertility from the transcriptome level in recent years ( Moye et al, 2019 ; Wang et al, 2019b ; Yuan et al, 2019 ; Goto, et al, 2020 ). KEGG pathway analysis results indicated that the pathways that DEGs might affect sperm development were mainly enriched in glycolysis/gluconeogenesis, protein processing in endoplasmic reticulum, carbon metabolism and cell cycle.…”

Section: Discussionmentioning

confidence: 99%

The Novel Key Genes of Non-obstructive Azoospermia Affect Spermatogenesis: Transcriptomic Analysis Based on RNA-Seq and scRNA-Seq Data

Fan

Wang

et al. 2021

Front. Genet.

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Non-obstructive azoospermia (NOA) is one of the most important causes of male infertility. It is mainly characterized by the absence of sperm in semen repeatedly or the number of sperm is small and not fully developed. At present, its pathogenesis remains largely unknown. The goal of this study is to identify hub genes that might affect biomarkers related to spermatogenesis. Using the clinically significant transcriptome and single-cell sequencing data sets on the Gene Expression Omnibus (GEO) database, we identified candidate hub genes related to spermatogenesis. Based on them, we performed Gene Ontology (GO) functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analyses, protein-protein interaction (PPI) network analysis, principal component analysis (PCA), cell cluster analysis, and pseudo-chronological analysis. We identified a total of 430 differentially expressed genes, of which three have not been reported related to spermatogenesis (C22orf23, TSACC, and TTC25), and the expression of these three hub genes was different in each type of sperm cells. The results of the pseudo-chronological analysis of the three hub genes indicated that TTC25 was in a low expression state during the whole process of sperm development, while the expression of C22orf23 had two fluctuations in the differentiating spermatogonia and late primary spermatocyte stages, and TSACC showed an upward trend from the spermatogonial stem cell stage to the spermatogenesis stage. Our research found that the three hub genes were different in the trajectory of sperm development, indicating that they might play important roles in different sperm cells. This result is of great significance for revealing the pathogenic mechanism of NOA and further research.

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Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice

Cited by 23 publications

References 49 publications

New clinical and molecular evidence linking mutations in ARSG to Usher syndrome type IV

New clinical and molecular evidence linking mutations in ARSG to Usher syndrome type IV

AutoMap is a high performance homozygosity mapping tool using next-generation sequencing data

The Novel Key Genes of Non-obstructive Azoospermia Affect Spermatogenesis: Transcriptomic Analysis Based on RNA-Seq and scRNA-Seq Data

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