Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.18/2157
Título: Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1
Autor: Lopes, Alexandra
Aston, Kenneth I.
Thompson, Emma E
Carvalho, Filipa
Gonçalves, João
Huang, N.
Matthiesen, Rune
Noordam, Michiel J.
Quintela, Ines
Ramu, Avinash
Seabra, Catarina
Wilfert, Amy B.
Dai, Juncheng
Downie, Jonathan
Fernandes, Susana
Guo, Xuejiang
Shah, Jiahao
Amorim, Antonio
Barros, Alberto
Carracedo, A.
Hu, Z.
Hurles, M.E.
Moskovtsev, S.
Ober, C.
Paduch, D.A.
Schiffman, J.D.
Schlegel, P.N.
Sousa, M.
Carrell, D.T.
Conrad, D.F.
Palavras-chave: Human Infertility
Human Spermatogenesis
Male Infertility
Doenças Genéticas
Data: 21-Mar-2013
Editora: Public Library of Science
Citação: PLoS Genet. 2013 Mar;9(3):e1003349. doi: 10.1371/journal.pgen.1003349. Epub 2013 Mar 21
Resumo: Gonadal failure, along with early pregnancy loss and perinatal death, may be an important filter that limits the propagation of harmful mutations in the human population. We hypothesized that men with spermatogenic impairment, a disease with unknown genetic architecture and a common cause of male infertility, are enriched for rare deleterious mutations compared to men with normal spermatogenesis. After assaying genomewide SNPs and CNVs in 323 Caucasian men with idiopathic spermatogenic impairment and more than 1,100 controls, we estimate that each rare autosomal deletion detected in our study multiplicatively changes a man’s risk of disease by 10% (OR 1.10 [1.04–1.16], p,261023), rare X-linked CNVs by 29%, (OR 1.29 [1.11–1.50], p,161023), and rare Y-linked duplications by 88% (OR 1.88 [1.13–3.13], p,0.03). By contrasting the properties of our case-specific CNVs with those of CNV callsets from cases of autism, schizophrenia, bipolar disorder, and intellectual disability, we propose that the CNV burden in spermatogenic impairment is distinct from the burden of large, dominant mutations described for neurodevelopmental disorders. We identified two patients with deletions of DMRT1, a gene on chromosome 9p24.3 orthologous to the putative sex determination locus of the avian ZW chromosome system. In an independent sample of Han Chinese men, we identified 3 more DMRT1 deletions in 979 cases of idiopathic azoospermia and none in 1,734 controls, and found none in an additional 4,519 controls from public databases. The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human spermatogenic failure (frequency of 0.38% in 1306 cases and 0% in 7,754 controls, p = 6.261025). Our study identifies other recurrent CNVs as potential causes of idiopathic azoospermia and generates hypotheses for directing future studies on the genetic basis of male infertility and IVF outcomes.
Peer review: yes
URI: http://hdl.handle.net/10400.18/2157
ISSN: 1553-7390
Versão do Editor: http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003349
Aparece nas colecções:DGH - Artigos em revistas internacionais

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