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Witch Nails Krt90whnl A spontaneous mouse mutation affecting nail growth and development

ABSTRACT: Numerous single gene mutations identified in humans and mice result in nail deformities with many similarities between the species. A spontaneous, autosomal, recessive mutation called witch nails whnl is described here where the distal nail matrix and nail bed undergo degenerative changes resulting in formation of an abnormal nail plate causing mice to develop long, curved nails. This mutation arose spontaneously in a colony of MRL MpJ-Faslpr J at The Jackson Laboratory. Homozygous mutant mice are recognizable by 8 weeks of age by their long, curved nails. The whnl mutation, mapped on Chromosome 15, is due to a 7-bp insertion identified in the 3 region of exon 9 in the Krt90 gene formerly Riken cDNA 4732456N10Rik, and is predicted to result in a frameshift that changes serine 476 to arginine and subsequently introduces 36 novel amino acids into the protein before a premature stop codon p. Ser476ArgfsTer36. By immunohistochemistry the normal KRT90 protein is expressed in the nail matrix and nail bed in control mice where lesions are located in mutant mice. Immunoreactivity toward equine KRT124, the ortholog of mouse KRT90, is restricted to the nail bed of the hoof and the mouse nail unit. Equine laminitis lesions are similar to those observed in this mutant mouse suggesting that the latter may be a useful model for this horse disease. This first spontaneous mouse mutation affecting the novel Krt90 gene provides new insight into the normal regulation of the molecular pathways of nail development.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Robert H. Rice

PROVIDER: MSV000089811 | MassIVE | Tue Jul 05 13:48:00 BST 2022

SECONDARY ACCESSION(S): PXD035095

REPOSITORIES: MassIVE

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Project description:We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. We have identified a patient born with WHIM syndrome and the WHIM mutation CXCR4R334X who has been disease-free for 20 years and who lacks CXCR4R334X in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele CXCR4R334X and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective Cxcr4 haploinsufficiency (inactivation of one copy of Cxcr4 and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that CXCR4 knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.

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Witch Nails Krt90whnl A spontaneous mouse mutation affecting nail growth and development

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