Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia
| Autor: | Alexandra M. Lopes, Eve Laasik, Lee B. Smith, Donald F. Conrad, Margus Punab, Filipa Carvalho, Marina Grigorova, Kenneth I. Aston, Laura Kasak, Ave Minajeva, Anna Maria Punab, Maris Laan, Liina Nagirnaja |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine congenital hereditary and neonatal diseases and abnormalities Loss of Heterozygosity Breast Neoplasms Biology Compound heterozygosity Article Frameshift mutation Sertoli cell-only syndrome Mice 03 medical and health sciences 0302 clinical medicine Fanconi anemia hemic and lymphatic diseases Testis Exome Sequencing Genetics medicine Animals Humans Genetic Predisposition to Disease Gene Silencing FANCM Frameshift Mutation Genetics (clinical) Exome sequencing Azoospermia Ovarian Neoplasms 030219 obstetrics & reproductive medicine Homozygote DNA Helicases Middle Aged medicine.disease Spermatozoa Pedigree Phenotype 030104 developmental biology medicine.anatomical_structure Codon Nonsense Female Germ cell |
| Zdroj: | The American Journal of Human Genetics. 103:200-212 |
| ISSN: | 0002-9297 7612-5041 |
| Popis: | Infertility affects around 7% of men worldwide. Idiopathic non-obstructive azoospermia (NOA) is defined as the absence of spermatozoa in the ejaculate due to failed spermatogenesis. There is a high probability that NOA is caused by rare genetic defects. In this study, whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS). Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition. A rare maternally inherited frameshift variant p.Gln498Thrfs∗7 (rs761250416) and a previously undescribed splicing variant (c.4387−10A>G) derived from the father introduce a premature STOP codon leading to a truncated protein. FANCM exhibits enhanced testicular expression. In control subjects, immunohistochemical staining localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development. This is consistent with its role in maintaining genomic stability in meiosis and mitosis. In the individual with SCOS carrying bi-allelic FANCM LoF variants, none or only faint expression was detected in the Sertoli cells. As further evidence, we detected two additional NOA-affected case subjects with independent FANCM homozygous nonsense variants, one from Estonia (p.Gln1701∗; rs147021911) and another from Portugal (p.Arg1931∗; rs144567652). The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia. FANCM pathogenic variants have also been linked with doubled risk of familial breast and ovarian cancer, providing an example mechanism for the association between infertility and cancer risk, supported by published data on Fancm mutant mouse models. |
| Databáze: | OpenAIRE |
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