Browsing by Author "Carvalho, Filipa"

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Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens
(ELSEVIER SCIENCE INC, 2010-01-01) Havasi, Viktoria; Rowe, Steven M.; Kolettis, Peter N.; Dayangac, Didem; Sahin, Ahmet; Grangeia, Ana; Carvalho, Filipa; Barros, Alberto; Sousa, Mario; Bassas, Lluis; Casals, Teresa; Sorscher, Eric J.
Objective: To investigate whether genetic modifiers of cystic fibrosis (CF) lung disease also predispose to congenital bilateral absence of the vas deferens (CBAVD) in association with cystic fibrosis transmembrane conductance regulator (CFTR) mutations. We tested the hypothesis that polymorphisms of transforming growth factor (TGF)-beta 1 (rs 1982073, rs 1800471) and endothelin receptor type A (EDNRA) (rs 5335, rs 1801708) are associated with the CBAVD phenotype. Design: Genotyping of subjects with clinical CBAVD. Setting: Outpatient and hospital-based clinical evaluation. Patient(s): DNA samples from 80 subjects with CBAVD and 51 healthy male controls from various regions of Europe. This is one of the largest genetic studies of this disease to date. Intervention(s): None. Main Outcome Measure(s): Genotype analysis. Result(s): For single nucleotide polymorphism (SNP) rs 5335, we found increased frequency of the CC genotype among subjects with CBAVD. The difference was significant among Turkish patients versus controls (45.2\% vs. 19.4\%), and between all cases versus controls (36\% vs. 15.7\%). No associations between CBAVD penetrance and polymorphisms rs 1982073, rs 1800471, or rs 1801708 were observed. Conclusion(s): Our findings indicate that endothelin receptor type A polymorphism rs 5335 may be associated with CBAVD penetrance. To our knowledge, this is the first study to investigate genetic modifiers relevant to CBAVD. (Fertil Steril (R) 2010
Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility
(CELL PRESS, 2020-01-01) Wyrwoll, Margot J.; Temel, Sehime G.; Nagirnaja, Liina; Oud, Manon S.; Lopes, Alexandra M.; van der Heijden, Godfried W.; Heald, James S.; Rotte, Nadja; Wistuba, Joachim; Woeste, Marius; Ledig, Susanne; Krenz, Henrike; Smits, Roos M.; Carvalho, Filipa; Goncalves, Joao; Fietz, Daniela; Turkgenc, Burcu; Ergoren, Mahmut C.; Cetinkaya, Murat; Basar, Murad; Kahraman, Semra; McEleny, Kevin; Xavier, Miguel J.; Turner, Helen; Pilatz, Adrian; Roepke, Albrecht; Dugas, Martin; Kliesch, Sabine; Neuhaus, Nina; Aston I, Kenneth; Conrad, Donald F.; Veltman, Joris A.; Friedrich, Corinna; Tuettelmann, Frank; Consortium, G. E. M. I. N. I.
Male infertility affects similar to 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. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. 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 has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.