An Autosomal Recessive Alopecia Areata Locus with Lymphoproliferative Syndrome in Mice

Maryam Alshareef1; Quan Li1; Constantin Polychronakos1*

Endocrine Genetics Laboratory, McGill University Health Center, Montreal Children’s Hospital Research Institute, McGill University, 2300 Tupper Street, Montreal, QC H3H 1P3, Canada,

Background: Alopecia areata (AA) consists of patchy hair loss and most human cases are due to autoimmunity against hair follicles. Lymphoproliferative syndromes are often associated with autoimmunity.

Objective: To characterize and genetically map a novel monogenic murine phenotype of AA and lymphoproliferation, arising spontaneously due to an autosomal recessive mutation.

Methods: Immunohistochemistry of skin and cell-surface marker phenotyping of immune cells, Whole-exome sequencing and linkage analysis

Results: The mutant mice have striking alopecia phenotype accompanied by drastically swelling cervical lymph nodes, enlarged spleen and body weight loss.

Histology and immunohistochemistry staining show that the hair loss is associated with T lymphocyte infiltration in the upper part of the hair follicle. Histological sections show evidence of epithelial and sebaceous gland hyperplasia in the affected skin. Flow cytomery analysis of cells from the enlarged cervical lymph nodes showed a significant association between alopecia phenotype and reduction of T and B-lymphocyte population and significant increase in the non-T cells populations and in the proliferation of T-cells.

Exome sequencing on two affected mice and one obligate heterozygote, identified a mutation in 5’UTR of the Ptprd gene that segregates very well with phenotype (LOD=8.3 at θ=0). However, the KO mice of Ptprd gene don’t have the same phenotype, making it very unlikely that this mutation is causative.

Conclusion: Autosomal recessive Alopecia-lymphoproliferation in mice maps to the Ptprd locus; however, the causative mutation, missed in the exome sequencing, must map to one of the neighbouring genes.