Sequencing of FTO and ALKBH5 in men undergoing infertility work-up identifies infertility associated variant and two missense mutations

Sequencing of the ALKBH5 and FTO genes in patients with male factor infertility identified one genetic variant in the FTO gene to be associated with reduced semen quality and two FTO missense variants.

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Miriam Landfors, M.Sc., Sigve Nakken, Ph.D., Markus Fusser, Ph.D., John-Arne Dahl, Ph.D., Arne Klungland, Ph.D., Peter Fedorcsak, Ph.D.

Volume 105, Issue 5, Pages 1170-1179



To assess whether men with reduced semen quality exhibit genetic variants in the genes coding for the messenger RNA methylation erasers FTO and ALKBH5.


DNA of men undergoing infertility work-up was extracted and the FTO and ALKBH5 genes were sequenced. Statistical analysis was used to study the correlation between the identified ALKBH5 and FTO variants and sperm quality.


University hospital infertility clinic.


Semen samples from 77 unselected men that had been referred to Oslo University Hospital for routine semen analysis as part of infertility work-up.


Not applicable.

Main Outcome Measure(s):

Immunohistochemistry and Western blot were used to confirm the presence of ALKBH5 and FTO in human testis. DNA extraction from samples was followed by Illumina MiSeq amplicon high throughput sequencing and sequence alignment. Variant calling was carried out using GATK’s UnifiedGenotyper. Standard semen parameter analysis was performed according to World Health Organization guidelines.


We found an FTO genetic variant to be associated with reduced semen quality. We also identified two FTO missense variants, one mutation (p.Cys326Ser) was located in the important linker between the two protein domains; the other mutation (p.Ser256Asn) was situated in a flexible loop able to interact with other molecules.


The discovery of two missense mutations with potentially detrimental effect on the functionality of the methylation eraser protein FTO, as well as a genetic variant of the same protein that is associated with altered semen quality could suggest that aberrant demethylation of messenger RNA is a factor involved in reduced male fertility.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.