Browsing by Author "Pereira, Iris"
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- AZF midrodeletions screening in infertile men of the Portuguese populationPublication . Pereira, Iris; Silva, Júlia; Correia, Sónia; Pinto, Maria Graça; Rangel, Ricardo; Aguiar, Ana; Nunes, Joaquim; Calhaz Jorge, Carlos; Gonçalves, JoãoAnalysis of genetic conditions associated with male infertility is, at present days, restricted to chromosome analysis, AZF Y-chromosome microdeletions screening, and to patients with hypogonadotrophic hypogonadism or with congenital absence of the vas deferens. Among different populations AZF microdeletions can explain 10-15% of the infertile phenotype of azoospermic men and 2-5% of oligozoospermic men. Here we present the results of AZF deletions screening performed in a selected group of infertile Portuguese men with idiopathic non-obstructive azoospermia or with oligozoospermia (men with other causes of male infertility, endocrinological alterations, varicocele, criptorquidism, professional risk factors, autosomal chromosomal abnormalities, were excluded for this study). Analysis was performed by Multiplex-PCR using specific STS for the three AZF regions. Microdeletion breakpoints were confirmed using a second multiplex-PCR. We analysed 865 infertile men (270 azospermic and 595 oligozoospermic with [spermatozoa]<5x106/mL) and 300 DNA samples obtained from fertile men of the Portuguese population. While AZF microdeletions were found in 27 azoospermic (10.0%) and in 22 oligozoospermic men (3.7%), in fertile men no microdeletions were detected.Our results demonstrate that AZF microdeletions are frequent among males with the infertile phenotype described above. The regions absent have prognostic value for the clinical decision and patients treatment. Genetic counselling is recommended to all patients with AZFdel. AZFcdel will be obligatorily transmitted to all male offspring by ICSI, which will seriously impair their fertility.
- Cancro colo-retal hereditário: pesquisa de mutações em famílias portuguesasPublication . Isidro, Glória; Theisen, Patrícia; Pereira, Iris; Gonçalves, João
- The mutational spectrum of WT1 in male infertilityPublication . Seabra, Catarina M.; Quental, Sofia; Lima, Ana C; Carvalho, Filipa; Gonçalves, João; Fernandes, Susana; Pereira, Iris; Silva, Júlia; Marques, Patrícia I.; Sousa, Mário; Barros, Alberto; Seixas, Susana; Amorim, António; Lopes, Alexandra M.PURPOSE: We evaluated the impact of WT1 mutations in isolated severe spermatogenic impairment in a population of European ancestry. WT1 was first identified as the gene responsible for Wilms tumor. It was later associated with a plethora of clinical phenotypes often accompanied by urogenital defects and male infertility. The recent finding of WT1 missense mutations in Chinese azoospermic males without major gonadal malformations broadened the phenotypic spectrum of WT1 defects and motivated this study. MATERIALS AND METHODS: We analyzed the WT1 coding region in a cohort of 194 Portuguese patients with nonobstructive azoospermia and in 188 with severe oligozoospermia with increased depth for the exons encoding the regulatory region of the protein. We also analyzed a group of 31 infertile males with a clinical history of unilateral or bilateral cryptorchidism and 1 patient with anorchia. RESULTS: We found 2 WT1 missense substitutions at higher frequency in patients than in controls. 1) A novel variant in exon 1 (p.Pro130Leu) that disrupted a mammalian specific polyproline stretch in the self-association domain was more frequent in azoospermia cases (0.27% vs 0.13%, p = 0.549). 2) A rare variant in a conserved residue in close proximity to the first zinc finger (pCys350Arg) was more frequent in severe oligozoospermia cases (0.80% vs 0.13%, p = 0.113). CONCLUSIONS: Results suggest a role for rare WT1 damaging variants in severe spermatogenic failure in populations of European ancestry. Large multicenter studies are needed to fully assess the contribution of WT1 genetic alterations to male infertility in the absence of other disease phenotypes.
- X-linked adrenal hipoplasia congenita: clinical and follow-up findings of two kindreds, one with a novel NR0B1 mutationPublication . Dias Pereira, Bernardo; Portugal, Jorge Ralha; Pereira, Iris; Gonçalves, João; Raimundo, LuísaX-linked adrenal hypoplasia congenita typically manifests as primary adrenal insufficiency in the newborn age and hypogonadotropic hypogonadism in males, being caused by mutations in NR0B1 gene. We present the clinical and follow-up findings of two kindreds with NR0B1 mutations. The proband of kindred A had a diagnosis of primary adrenal insufficiency when he was a newborn. Family history was relevant for a maternal uncle death at the newborn age. Beyond 2 year-old steroid measurements rendered undetectable and delayed bone age was noticed. Molecular analysis of NR0B1 gene revealed a previously unreported mutation (c.1084A>T), leading to a premature stop codon, p.Lys362*, in exon 1. His mother and sister were asymptomatic carriers. At 14 year-old he had 3 mL of testicular volume and biochemical surveys (LH < 0.1 UI/L, total testosterone < 10 ng/dL) concordant with hypogonadotrophic hypogonadism. Kindred B had two males diagnosed with adrenal insufficiency at the newborn age. By 3 year-old both siblings had undetectable androgen levels and delayed bone age. NR0B1 molecular analysis identified a nonsense mutation in both cases, c.243C>G; p.Tyr81*, in exon 1. Their mother and sister were asymptomatic carriers. At 14 year-old (Tanner stage 1) hypothalamic-pituitary-gonadal axis evaluation in both males (LH < 0.1UI/L, total testosterone < 10 ng/dL) confirmed hypogonadotropic hypogonadism. In conclusion, biochemical profiles, bone age and an X-linked inheritance led to suspicion of NR0B1 mutations. Two nonsense mutations were detected in both kindreds, one previously unreported (c.1084A>T; p.Lys362*). Mutation identification allowed the timely institution of testosterone in patients at puberty and an appropriate genetic counselling for relatives.