DNA database provides evidence to preclude linkage of PIWI1 mutations to human male infertility

Lead researcher

Professor Rob McLachlan, the Hudson Institute author and is one of a number of international researchers who have published this study.

Main finding

A genetic basis for male infertility is an active area of research worldwide. Many genes have been proposed based on animal models but few have proven relevant to the human. It is important that candidate mutations be rigorously assessed before they earn a place in the clinical evaluation. Recently the list of causative mutations in male infertility has been increasing rapidly.
The piwi-like RNA-mediated gene silencing 1 (PIWIL1; also known as HIWI) gene is involved in spermatid chromosome modelling, and a mutation in its D box area has been linked to azoospermia in animals and the human by Gou et al [Cell Research; 2017].
This current paper sought to establish whether this gene is indeed relevant to human male infertility, and represents a major international collaborative effort run from the Dept of Human Genetics at Radboud University in the Netherlands, along with numerous other European, UK and American centres, and Monash University/Hudson Institute.
The Monash Male Infertility DNA database, developed over the past 25 years, was utilised to contribute many clinical samples to the overall study of 1950 azoospermic and 790 severely oligospermic men. No PIWIL1 D box mutations were found as proposed by the previous authors. The study investigators went on to explore potential variants elsewhere in the gene and, while some minor variants were found, these were at no greater rate as compared to 3347 controls. There were several heterozygous loss of function variants seen, including in control men, and it was considered unlikely that they would likely cause disease in the haploinsufficient state.
This is an important negative study which has excluded mutations in the D box region of the PIWIL1 gene as a cause of human azoospermia. Such vigilance is important in developing clinical testing panels.

Centre

Centre for Endocrinology and Metabolism

Research group

Clinical Andrology

Co-authors

Dr Manon Oud, Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands
Dr Ludmila Volozonoka, Scientific Laboratory of Molecular Genetics, Riga Stradins University, LV-1007, Riga, Latvia
Dr Corinna Friedrich, Institute of Reproductive Genetics, University of Münster, Münster, Germany
Prof Sabine Kliesch, Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Münster, Münster, Germany
Dr Liina Nagirnaja, Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA
Assoc Professor Christian Gilissen, Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands
Professor Moira O’Bryan, School of Biological Sciences, Monash University, Clayton, Melbourne, Australia & School of BioSciences, Faculty of Science, The University of Melbourne, Parkville, Melbourne, Australia
Professor Rob McLachlan, Hudson Institute of Medical Research, Clayton, Melbourne, Australia & Department of Obstetrics and Gynecology, Monash University, Clayton, Melbourne, Australia
Assoc Professor Kenneth Aston, Division of Urology, Department of Surgery, University of Utah, Salt Lake City, UT, USA
Professor Frank Tüttelmann, Institute of Reproductive Genetics, University of Münster, Münster, Germany
Assoc Professor Donald, Conrad Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA
Professor Joris Veltman, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

Journal and article title

Cell

Lack of evidence for a role of PIWIL1 variants in human male infertility

Most surprising

The results were not surprising as such. There have been many candidate genes for causes of infertility, some of which have been eliminated as contenders on closer investigation, like this one. The findings are not novel but are important, as indicated by their publication in such a high impact journal.

Future implications

Infertility can be most distressing for many people who are unable to have children, particularly when the cause is not known. The more information that is known about the causes of infertility, the more hope there will be for treatments to be developed to assist people who are unable to conceive children. This study provides information about one gene that had been proposed as a cause of male infertility. The quality of life of people experiencing infertility will be improved by studies such as this which allow focus to be directed to the genes that may be causative of the condition.

Disease/health impact

Human male infertility

Other points of interest

The study is a major international collaborative effort run from the Department of Human Genetics at Radboud University in the Netherlands, along with numerous other European, UK and American centres, and Monash University/Hudson Institute.
Professor Rob McLachlan’s involvement in this study is clinical sample acquisition over many decades as well as clinical input. The driving force for the Australian contingent of this international collaboration is Professor Moira O’Bryan, formerly of MIMR and Monash University, and currently of the University of Melbourne.