Abstract
Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the CTNS gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease-modifying treatment. We aimed at unraveling the origin of azoospermia in cysteamine-treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the Ctns-/- mouse model compared with wild type. Azoospermia was present in the vast majority of infantile type cystinosis patients. While spermatogenesis was intact, an enlarged caput epididymis and reduced levels of seminal markers for obstruction neutral α-glucosidase (NAG) and extracellular matrix protein 1 (ECM1) pointed towards an epididymal obstruction. Histopathological examination in human and mouse testis revealed a disturbed blood-testis barrier characterized by an altered zonula occludens-1 (ZO-1) protein expression. Animal studies ruled out a negative effect of cysteamine on fertility, but showed that cystine accumulation in the testis is irresponsive to regular cysteamine treatment. We conclude that the azoospermia in infantile cystinosis is due to an obstruction related to epididymal dysfunction, irrespective of the severity of an evolving primary hypogonadism. Regular cysteamine treatment does not affect fertility but has subtherapeutic effects on cystine accumulation in testis.
| Original language | English |
|---|---|
| Pages (from-to) | 1393-1408 |
| Number of pages | 16 |
| Journal | Journal of Inherited Metabolic Disease |
| Volume | 44 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Nov 2021 |
Bibliographical note
Funding Information:Cystinosis Ireland; Foundation of Scientific Research Flanders, Grant/Award Numbers: 1801110N, 11Y5216N; Cystinosis Research Foundation Funding information
Funding Information:
The authors would like to thank the funding organization, Cystinosis Ireland, HRCI/HRB Joint Funding Scheme. The authors would like also to thank all the participants (patients and control individuals) who volunteered in the study, the group of Prof Corinne Antignac for providing us with the cystinosis mouse model, Prof Karen Boyle for collaborating during the clinical study, Prof Francesco Emma for giving us the opportunity to perform part of the animal studies in his lab, and technical support by Pascale Bols and Elly Vergison, fertility center, department of gynecology, UZ Leuven. Cysteamine plasma and tissue levels were evaluated in University of California San Diego (UCSD) Biochemical Genetics and Metabolomics Laboratory, California, by Dr Ilya Gertsman and Dr Jon Gangoiti. Library preparation, sequencing and statistical data analysis were performed in VIB Nucleomics Core (www.nucleomics.be) by Dr Rekin's Janky. This work was supported by Cystinosis Ireland, a member of Health Research Charities Ireland (HRCI) that participates in the HRCI/HRB (Health Research Board) Joint Funding Scheme (previously known as the medical research charities group-HRB Joint Funding Scheme (MRCG/HRB)), Dublin, Ireland. Anna Taranta and Laura Rita Rega were supported by Cystinosis Research Foundation (CRF). Elena Levtchenko and Koenraad Veys were funded by Foundation of Scientific Research Flanders (FWO Vlaanderen, grants 11Y5216N and 1801110N, respectively).
Funding Information:
The authors would like to thank the funding organization, Cystinosis Ireland, HRCI/HRB Joint Funding Scheme. The authors would like also to thank all the participants (patients and control individuals) who volunteered in the study, the group of Prof Corinne Antignac for providing us with the cystinosis mouse model, Prof Karen Boyle for collaborating during the clinical study, Prof Francesco Emma for giving us the opportunity to perform part of the animal studies in his lab, and technical support by Pascale Bols and Elly Vergison, fertility center, department of gynecology, UZ Leuven. Cysteamine plasma and tissue levels were evaluated in University of California San Diego (UCSD) Biochemical Genetics and Metabolomics Laboratory, California, by Dr Ilya Gertsman and Dr Jon Gangoiti. Library preparation, sequencing and statistical data analysis were performed in VIB Nucleomics Core ( www.nucleomics.be ) by Dr Rekin's Janky. This work was supported by Cystinosis Ireland, a member of Health Research Charities Ireland (HRCI) that participates in the HRCI/HRB (Health Research Board) Joint Funding Scheme (previously known as the medical research charities group‐HRB Joint Funding Scheme (MRCG/HRB)), Dublin, Ireland. Anna Taranta and Laura Rita Rega were supported by Cystinosis Research Foundation (CRF). Elena Levtchenko and Koenraad Veys were funded by Foundation of Scientific Research Flanders (FWO Vlaanderen, grants 11Y5216N and 1801110N, respectively).
Publisher Copyright:
© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.