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. Author manuscript; available in PMC: 2014 Jul 1.
Published in final edited form as: J Invest Dermatol. 2013 Jun 17;134(1):279–281. doi: 10.1038/jid.2013.273

Mouse Alopecia Areata and Heart Disease: Know Your Mouse!

John P Sundberg 1,3, Lucie Chevallier 1, Kathleen A Silva 1, Victoria E Kennedy 1, Beth A Sundberg 1, Qiaoli Li 2, Jouni Uitto 2, Lloyd E King Jr 3, Annerose Berndt 4
PMCID: PMC3825791  NIHMSID: NIHMS492762  PMID: 23774530

To the editor

The proceedings of a recent meeting on alopecia areata (AA) (Bertolini et al., 2012) summarized work using the surgically induced C3H/HeJ mouse model for AA (McElwee et al., 1998), in which investigators found enlarged hearts in affected mice, suggesting an association between AA and cardiac findings. However, the heart lesions described are a well known strain specific disease, not limited to C3H substrains. These lesions have been described by a number of names including epicardial mineralization with fibrosis and dystrophic cardiac calcinosis (Eaton et al., 1978; Frith and Ward, 1988). Crosses between C3H/HeJ and C57BL/6J mice have identified 4 quantitative trait loci (QTLs), designated as Dystrophic Cardiac Calcinosis 1-4 (Dyscalc1-4) (Ivandic et al., 2001). Mapping to mouse Chr. 7 (Ivandic et al., 1996), Dyscalc1 was subsequently identified as being due to non-synonymous single nucleotide polymorphisms in the ATP-binding cassette, sub-family C (CFTR/MRP), member 6 (Abcc6) gene (Aherrahrou et al., 2008; Meng et al., 2007). Mutations in the human ABCC6 gene and targeted mutations in the mouse Abcc6 gene produce pseudoxanthoma elasticum (PXE) (Gorgels et al., 2005; Klement et al., 2005), a systemic metabolic disease with cutaneous features distinct from AA (Uitto et al., 2010).

In a massive histopathological screening of all organ systems in 31 inbred strains of mice of both genders, dystrophic cardiac calcinosis was diagnosed in 8 strains (Berndt et al., submitted; Sundberg et al., 2011). C3H/HeJ and A/J strains were found to develop both heart lesions (Chase et al., 2009) and AA (McElwee et al., 1999) in the aging study, although in both cases more mice with normal skin had heart lesions than those with AA (Table 1a). Three strains were found to develop histologically confirmed AA (MRL/MpJ, SJL/J, and SWR/J) but none of these mice had any type of heart lesion. No correlation was found in a retired breeder study (Table 1b) (Berndt et al., submitted) or in a large mouse cross (C3H/HeJ x C57BL/6J, C3B6F2; Table 1c) generating F2 females for identifying AA eQTLs. Heart lesions varied in severity and location between the strains (Berndt et al., submitted). Genome-wide association mapping determined that none of the QTLs for dystrophic cardiac calcinosis corresponded to genomic regions identified to determine AA.

Table 1. Lack of correlation between dystrophic cardiac calcinosis in aging mouse strains and adult onset alopecia areata.

There was no correlation between histologically confirmed alopecia areata and dystrophic cardiac calcinosis in 31 inbred strains in an aging histopathology study (a), evaluation of hearts in retired breeders (b), or F2 hybrid study for mapping quantitative trait loci for alopecia areata (c).

Table 1a. There was no correlation between alopecia areata and heart lesions in mouse strains in the 31 strain aging study.
Strain Total Mice 12 & 20 mo. moribund Alopecia Areata Dystrophic Cardiac Calcinosis Normal Skin Dystrophic Cardiac Calcinosis
Gender: Fe M Fe M Fe M Fe M Fe M
A/J 51 46 0 1 0 0 51 45 23 8
C3H/HeJ 28 29 7 3 0 0 21 26 1 3
MRL/MpJ 41 31 2 0 0 0 39 31 0 0
SJL/J 36 10 2 0 0 0 34 10 0 0
SWR/J 24 18 6 0 0 0 18 18 0 0
Total: 180 134 17 4 0 0 163 130 24 11
Table 1b. Alopecia areata was not diagnosed in any of the strains in the retired breeder survey.
Strain Total Alopecia Areata Dystrophic Cardiac Calcinosis Strain Total Alopecia Areata Dystrophic Cardiac Calcinosis
Gender: Fe M Fe M Fe M Gender: Fe M Fe M Fe M
A/J 10 10 0 0 9 10 DBA/2J 10 10 0 0 10 10
BALB/cJ 10 10 0 0 9 10 FVB/NJ 10 10 0 0 0 0
BALB/cByJ 10 10 0 0 8 10 KK/HlJ 10 10 0 0 10 9
C3H/HeJ 10 10 0 0 10 6 LP/J 10 10 0 0 0 0
C57BL/6J 10 10 0 0 0 1 PWD/PhJ 10 10 0 0 0 0
C57BL/10J 10 10 0 0 7 10 SWR/J 10 10 0 0 0 0
Total: 60 60 0 0 43 47 Total: 60 60 0 0 20 19
Table 1c. There was no correlation between alopecia areata and heart disease in an F2 hybrid cross used to investigate the genetics of these diseases (p-value = 0.651 using a Fisher exact test).
Strain Age Range (d) Gender Alopecia Areata DCC Normal Skin DCC
C3B6F2 195–605 Female 191 1 145 4
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While it is easy to see clinical correlations between seemingly unrelated diseases in small numbers of mice undergoing experimental manipulation, it is critically important to understand strain specific background lesions. The mineralization and fibrosis phenomena among the inbred strains associated with PXE-like diseases are very complicated. Some are related to each other while others are not. The underlying genetic predisposition can be modified by the genes involved in other diseases. Such appears to be the case for Abcc6 and PXE (Berndt et al., 2013). As the complex genetics of AA in humans and mice continues to be refined, it is possible that some of the genes involved in development of heart lesions may overlap with those that determine AA, but with technologies currently available using large populations of mice it appears that cardiac mineralization and fibrosis phenotypes are not correlated with AA.

Acknowledgments

Grants: Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number AR056635. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Berndt is the recipient of a fellowship by the Parker B. Francis Foundation and recipient of a North American Hair Research Society Mentorship Grant. The Jackson Laboratory Shared Scientific Services were supported in part by a Basic Cancer Center Core Grant from the National Cancer Institute (CA34196).

Abbreviations

AA

alopecia areata

Abcc6 (mouse gene)

ABCC6 (human gene), ATP-binding cassette subfamily C, member 6, gene

Dyscalc1-4

dystrophic cardiac calcinosis 1-4, quantitative trait loci

PXE

pseudoxanthoma elasticum

QTL

quantitative trait loci

Footnotes

Conflict of interest: none to declare

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