Browsing by Author "Carvalho, F."
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- Biallelic mutations in M1AP are associated with meiotic arrest, severely impaired spermatogenesis and male infertilityPublication . Friedrich, C.; Temel, S.G.; Nagirnaja, L.; Oud, M.S.; Lopes, A.M.; van der Heijden, G.W.; Heald, J.; Rotte, N.; Heald, J.; Rotte, N.; Wistuba, J.; Wöste, M.; Ledig, S.; Krenz, H.; Smits, R.M.; Carvalho, F.; Gonçalves, João; Fietz, D.; Türkgenç, B.; Ergören, M.C.; Çetinkaya, M.; Başar, M.; Kahraman, S.; McEleny, K.; Xavier, M.J.; Turner, H.; Pilatz, A.; Röpke, A.; Dugas, M.; Kliesch, S.; Neuhaus, N.; GEMINI Consortium; Aston, K.I.; Conrad, D.F.; Veltman, J.A.; Wyrwoll, M.J.; Tüttelmann, F.Male infertility affects ~7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis, but so far only few validated causal genes have been reported. To address this gap, we performed whole exome sequencing in 58 men with unexplained meiotic arrest and identified in three unrelated men the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 arresting protein. This variant results in a truncated protein lacking 57% of its full-length as shown in vitro by heterologous expression of mutated M1AP. Next, we screened four large cohorts of 1904 infertile men from the International Male Infertility Genomics Consortium (IMIGC) and identified three additional cases carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant p.(Pro389Leu) segregated with infertility in five men from a consanguineous Turkish family (LOD score = 3.28). The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype was described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP cause autosomal recessive severe spermatogenic failure and male infertility. In view of the evidences from several independent groups and populations, M1AP should be included in the growing list of validated male infertility genes.
- Rare double sex and mab-3-related transcription factor 1 regulatory variants in severe spermatogenic failurePublication . Lima, A.C.; Carvalho, F.; Gonçalves, J.; Fernandes, S.; Marques, P.I.; Sousa, M.; Barros, A.; Seixas, A.; Amorim, A.; Conrad, D.F.; Lopes, M.The double sex and mab-3-related transcription factor 1 (DMRT1) gene has long been linked to sex-determining pathways across vertebrates and is known to play an essential role in gonadal development and maintenance of spermatogenesis in mice. In humans, the genomic region harboring the DMRT gene cluster has been implicated in disorders of sex development and recently DMRT1 deletions were shown to be associated with non-obstructive azoospermia (NOA). In this work, we have employed different methods to screen a cohort of Portuguese NOA patients for DMRT1 exonic insertions and deletions [by multiplex ligation probe assay (MLPA); n = 68] and point mutations (by Sanger sequencing; n = 155). We have found three novel patient-specific non-coding variants in heterozygosity that were absent from 357 geographically matched controls. One of these is a complex variant with a putative regulatory role (c.-223_-219CGAAA>T), located in the promoter region within a conserved sequence involved in Dmrt1 repression. Moreover, while DMRT1 domains are highly conserved across vertebrates and show reduced levels of diversity in human populations, two rare synonymous substitutions (rs376518776 and rs34946058) and two rare non-coding variants that potentially affect DMRT1 expression and splicing (rs144122237 and rs200423545) were overrepresented in patients when compared with 376 Portuguese controls (301 fertile and 75 normozoospermic). Overall our previous and present results suggest a role of changes in DMRT1 dosage in NOA potentially also through a process of gene misregulation, even though DMRT1 deleterious variants seem to be rare.