Abstract
Chediak-Higashi Syndrome (CHS) is a well-characterized, autosomal recessively inherited lysosomal disease caused by mutations in lysosomal trafficking regulator (LYST). The feline model for CHS was originally maintained for ~20 years. However, the colonies were disbanded and the CHS cat model was lost to the research community before the causative mutation was identified. To resurrect the cat model, semen was collected and cryopreserved from a lone, fertile, CHS carrier male. Using cryopreserved semen, laparoscopic oviductal artificial insemination was performed on three queens, two queens produced 11 viable kittens. To identify the causative mutation, a fibroblast cell line, derived from an affected cat from the original colony, was whole genome sequenced. Visual inspection of the sequence data identified a candidate causal variant as a ~20 kb tandem duplication within LYST, spanning exons 30 through to 38 (NM_001290242.1:c.8347-2422_9548 + 1749dup). PCR genotyping of the produced offspring demonstrated three individuals inherited the mutant allele from the CHS carrier male. This study demonstrated the successful use of cryopreservation and assisted reproduction to maintain and resurrect biomedical models and has defined the variant causing Chediak-Higashi syndrome in the domestic cat.
Highlights
Chediak-Higashi syndrome (CHS) (OMIM Accession: 214500) is a rare autosomal recessive disorder characterized in humans by severe immune deficiency, oculocutaneous albinism, bleeding tendencies, recurrent pyogenic infections, progressive neurologic defects and a lymphoproliferative syndrome
Chediak-Higashi Syndrome is a well-characterized lysosomal disease caused by mutations in lysosomal trafficking regulator (LYST)
Other diseases associated with the regulation of lysosome-related organelles (LROs) size and/or vesicle trafficking, such as asthma, urticaria and Leishmania amazonensis infections, could benefit from understanding the molecular function of LYST and identification of its interacting www.nature.com/scientificreports partners may provide therapeutic targets[64]
Summary
Chediak-Higashi syndrome (CHS) (OMIM Accession: 214500) is a rare autosomal recessive disorder characterized in humans by severe immune deficiency, oculocutaneous albinism, bleeding tendencies, recurrent pyogenic infections, progressive neurologic defects and a lymphoproliferative syndrome. The human homolog of the mouse beige locus revealed the first causative mutations for CHS in humans[37,38] and was defined as lysosomal trafficking regulator (LYST)[37]. In many species with CHS, mutations have been consistently identified within LYST These species include, human[39,40,41,42], cow[43], mouse[44,45], rat[46,47] and Aleutian mink[48]. Whole genome sequencing of fibroblast cell-lines derived from the original CHS cat colony helped identify a candidate causative mutation, a 20 kb tandem segmental duplication within LYST that spanned multiple exons. Viable AI offspring were screened for the causative variant, demonstrating successful resurrection of a previously extinct feline model of a human disease and stability of the LYST mutation
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