FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / G3 (Bethesda) / An Intronic MBTPS2 Variant Results in a Splicing Defect in H...
G3 (Bethesda, Md.)2016; 6(9); 2963-2970; doi: 10.1534/g3.116.032433

An Intronic MBTPS2 Variant Results in a Splicing Defect in Horses with Brindle Coat Texture.

Abstract: We investigated a family of horses exhibiting irregular vertical stripes in their hair coat texture along the neck, back, hindquarters, and upper legs. This phenotype is termed "brindle" by horse breeders. We propose the term "brindle 1 (BR1)" for this specific form of brindle. In some BR1 horses, the stripes were also differentially pigmented. Pedigree analyses were suggestive of a monogenic X-chromosomal semidominant mode of inheritance. Haplotype analyses identified a 5 Mb candidate region on chromosome X. Whole genome sequencing of four BR1 and 60 nonbrindle horses identified 61 private variants in the critical interval, none of them located in an exon of an annotated gene. However, one of the private variants was close to an exon/intron boundary in intron 10 of the MBTPS2 gene encoding the membrane bound transcription factor peptidase, site 2 (c.1437+4T>C). Different coding variants in this gene lead to three related genodermatoses in human patients. We therefore analyzed MBTPS2 transcripts in skin, and identified an aberrant transcript in a BR1 horse, which lacked the entire exon 10 and parts of exon 11. The MBTPS2:c1437+4T>C variant showed perfect cosegregation with the brindle phenotype in the investigated family, and was absent from 457 control horses of diverse breeds. Altogether, our genetic data, and previous knowledge on MBTPS2 function in the skin, suggest that the identified MBTPS2 intronic variant leads to partial exon skipping, and causes the BR1 phenotype in horses.
Copyright © 2016 Murgiano et al.
Get Full Text
Publication Date: 2016-09-08 PubMed ID: 27449517PubMed Central: PMC5015953DOI: 10.1534/g3.116.032433Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article explores a specific genetic variant in horses that results in a unique brindle coat texture, characterized by irregular vertical stripes. The study identifies this variant as linked to the MBTPS2 gene.

Research Process

  • The study began with an examination of a family of horses showing a unique pattern on their coat – irregular vertical stripes termed “brindle” by horse breeders. The study proposed to call this particular form “brindle 1” (BR1).
  • In some instances, these stripes also displayed differential pigmentation. Pedigree analysis suggested that inheritance followed a monogenic X-chromosomal semidominant pattern.
  • Via haplotype analyses, a 5 Mb candidate region on chromosome X was identified.
  • The researchers then sequenced the whole genome of four BR1 horses and 60 nonbrindle horses. This process identified 61 private variants located within the critical interval. Notably, none of these were located in an exon of an annotated gene.

Key Findings

  • Among the identified variants, one close to the exon/intron boundary in intron 10 of the MBTPS2 gene – coded as c.1437+4T>C – drew interest. The MBTPS2 gene codes the membrane bound transcription factor peptidase, site 2. Variants in this gene are known to cause three related genodermatoses in humans. Therefore, the researchers decided to analyze the MBTPS2 transcripts in the skin of the horses.
  • Analysis revealed that a BR1 horse showed an aberrant transcript which lacked the entirety of exon 10 and parts of exon 11. This specific MBTPS2:c1437+4T>C variant displayed perfect cosegregation with the brindle phenotype in the studied horse family and was absent from 457 control horses of diverse breeds.

Conclusions

  • All evidence gathered, when evaluated against knowledge about MBTPS2 function in the skin, leads the researchers to suggest that the identified MBTPS2 intronic variant brings about the skipping of part of the exon, thereby causing the BR1 phenotype in horses.

Cite This Article

APA
Murgiano L, Waluk DP, Towers R, Wiedemar N, Dietrich J, Jagannathan V, Drögemüller M, Balmer P, Druet T, Galichet A, Penedo MC, Müller EJ, Roosje P, Welle MM, Leeb T. (2016). An Intronic MBTPS2 Variant Results in a Splicing Defect in Horses with Brindle Coat Texture. G3 (Bethesda), 6(9), 2963-2970. https://doi.org/10.1534/g3.116.032433

Publication

G3 (Bethesda, Md.)
ISSN: 2160-1836
NlmUniqueID: 101566598
Country: England
Language: English
Volume: 6
Issue: 9
Pages: 2963-2970

Researcher Affiliations

Murgiano, Leonardo
  • Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, 4000 Belgium.
Waluk, Dominik P
  • Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Switzerland.
Towers, Rachel
  • Institute of Medical Genetics, Cardiff University, CF14 4XN, UK.
Wiedemar, Natalie
  • Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
Dietrich, Joëlle
  • Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
Jagannathan, Vidhya
  • Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
Drögemüller, Michaela
  • Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
Balmer, Pierre
  • Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Switzerland Division of Clinical Dermatology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
Druet, Tom
  • Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, 4000 Belgium.
Galichet, Arnaud
  • Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Switzerland.
Penedo, M Cecilia
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, California 95617-1102.
Müller, Eliane J
  • Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Department of Clinical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Switzerland Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3001 Switzerland Clinic for Dermatology, Inselspital, Bern University Hospital, 3010 Switzerland.
Roosje, Petra
  • Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Division of Clinical Dermatology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Switzerland.
Welle, Monika M
  • Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland Institute of Medical Genetics, Cardiff University, CF14 4XN, UK.
Leeb, Tosso
  • Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland tosso.leeb@vetsuisse.unibe.ch.

MeSH Terms

  • Animals
  • Exons / genetics
  • Hair / growth & development
  • Hair / metabolism
  • Horses / genetics
  • Humans
  • Introns / genetics
  • Metalloendopeptidases / genetics
  • Phenotype
  • RNA Splicing / genetics
  • Skin Diseases / genetics
  • Skin Diseases / pathology
  • X Chromosome / genetics

References

This article includes 32 references
  1. Aten E, Brasz LC, Bornholdt D, Hooijkaas IB, Porteous ME, Sybert VP, Vermeer MH, Vossen RH, van der Wielen MJ, Bakker E, Breuning MH, Grzeschik KH, Oosterwijk JC, den Dunnen JT. Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2.. Hum Mutat 2010 Oct;31(10):1125-33.
    pubmed: 20672378doi: 10.1002/humu.21335google scholar: lookup
  2. Bornholdt D, Atkinson TP, Bouadjar B, Catteau B, Cox H, De Silva D, Fischer J, Gunasekera CN, Hadj-Rabia S, Happle R, Holder-Espinasse M, Kaminski E, König A, Mégarbané A, Mégarbané H, Neidel U, Oeffner F, Oji V, Theos A, Traupe H, Vahlquist A, van Bon BW, Virtanen M, Grzeschik KH. Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2.. Hum Mutat 2013 Apr;34(4):587-94.
    pubmed: 23316014doi: 10.1002/humu.22275google scholar: lookup
  3. Carmel I, Tal S, Vig I, Ast G. Comparative analysis detects dependencies among the 5' splice-site positions.. RNA 2004 May;10(5):828-40.
    pmc: PMC1370573pubmed: 15100438doi: 10.1261/rna.5196404google scholar: lookup
  4. Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L, Land SJ, Lu X, Ruden DM. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.. Fly (Austin) 2012 Apr-Jun;6(2):80-92.
    pmc: PMC3679285pubmed: 22728672doi: 10.4161/fly.19695google scholar: lookup
  5. Drögemüller C, Karlsson EK, Hytönen MK, Perloski M, Dolf G, Sainio K, Lohi H, Lindblad-Toh K, Leeb T. A mutation in hairless dogs implicates FOXI3 in ectodermal development.. Science 2008 Sep 12;321(5895):1462.
    pubmed: 18787161doi: 10.1126/science.1162525google scholar: lookup
  6. Drögemüller M, Jagannathan V, Becker D, Drögemüller C, Schelling C, Plassais J, Kaerle C, Dufaure de Citres C, Thomas A, Müller EJ, Welle MM, Roosje P, Leeb T. A mutation in the FAM83G gene in dogs with hereditary footpad hyperkeratosis (HFH).. PLoS Genet 2014;10(5):e1004370.
    pmc: PMC4022470pubmed: 24832243doi: 10.1371/journal.pgen.1004370google scholar: lookup
  7. Druet T, Georges M. LINKPHASE3: an improved pedigree-based phasing algorithm robust to genotyping and map errors.. Bioinformatics 2015 May 15;31(10):1677-9.
    pubmed: 25573918doi: 10.1093/bioinformatics/btu859google scholar: lookup
  8. Feingold KR, Elias PM. Role of lipids in the formation and maintenance of the cutaneous permeability barrier.. Biochim Biophys Acta 2014 Mar;1841(3):280-94.
    pubmed: 24262790doi: 10.1016/j.bbalip.2013.11.007google scholar: lookup
  9. Grzeschik KH, Bornholdt D, Oeffner F, König A, del Carmen Boente M, Enders H, Fritz B, Hertl M, Grasshoff U, Höfling K, Oji V, Paradisi M, Schuchardt C, Szalai Z, Tadini G, Traupe H, Happle R. Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia.. Nat Genet 2007 Jul;39(7):833-5.
    pubmed: 17546031doi: 10.1038/ng2052google scholar: lookup
  10. Haghighi A, Scott CA, Poon DS, Yaghoobi R, Saleh-Gohari N, Plagnol V, Kelsell DP. A missense mutation in the MBTPS2 gene underlies the X-linked form of Olmsted syndrome.. J Invest Dermatol 2013 Feb;133(2):571-3.
    pubmed: 22931912doi: 10.1038/jid.2012.289google scholar: lookup
  11. Happle R. X-chromosome inactivation: role in skin disease expression.. Acta Paediatr Suppl 2006 Apr;95(451):16-23.
    pubmed: 16720460doi: 10.1080/08035320600618775google scholar: lookup
  12. Happle R. The categories of cutaneous mosaicism: A proposed classification.. Am J Med Genet A 2016 Feb;170A(2):452-459.
    pubmed: 26494396doi: 10.1002/ajmg.a.37439google scholar: lookup
  13. Jagannathan V, Bannoehr J, Plattet P, Hauswirth R, Drögemüller C, Drögemüller M, Wiener DJ, Doherr M, Owczarek-Lipska M, Galichet A, Welle MM, Tengvall K, Bergvall K, Lohi H, Rüfenacht S, Linek M, Paradis M, Müller EJ, Roosje P, Leeb T. A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation.. PLoS Genet 2013;9(10):e1003848.
    pmc: PMC3789836pubmed: 24098150doi: 10.1371/journal.pgen.1003848google scholar: lookup
  14. Kere J, Srivastava AK, Montonen O, Zonana J, Thomas N, Ferguson B, Munoz F, Morgan D, Clarke A, Baybayan P, Chen EY, Ezer S, Saarialho-Kere U, de la Chapelle A, Schlessinger D. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein.. Nat Genet 1996 Aug;13(4):409-16.
    pubmed: 8696334doi: 10.1038/ng0895-409google scholar: lookup
  15. Kroos L, Akiyama Y. Biochemical and structural insights into intramembrane metalloprotease mechanisms.. Biochim Biophys Acta 2013 Dec;1828(12):2873-85.
    pmc: PMC3793210pubmed: 24099006doi: 10.1016/j.bbamem.2013.03.032google scholar: lookup
  16. Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data.. Bioinformatics 2011 Nov 1;27(21):2987-93.
    pmc: PMC3198575pubmed: 21903627doi: 10.1093/bioinformatics/btr509google scholar: lookup
  17. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform.. Bioinformatics 2009 Jul 15;25(14):1754-60.
    pmc: PMC2705234pubmed: 19451168doi: 10.1093/bioinformatics/btp324google scholar: lookup
  18. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.. Genome Res 2010 Sep;20(9):1297-303.
    pmc: PMC2928508pubmed: 20644199doi: 10.1101/gr.107524.110google scholar: lookup
  19. Molho-Pessach V, Schaffer JV. Blaschko lines and other patterns of cutaneous mosaicism.. Clin Dermatol 2011 Mar-Apr;29(2):205-25.
    pubmed: 21396561doi: 10.1016/j.clindermatol.2010.09.012google scholar: lookup
  20. Murgiano L, Shirokova V, Welle MM, Jagannathan V, Plattet P, Oevermann A, Pienkowska-Schelling A, Gallo D, Gentile A, Mikkola M, Drögemüller C. Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation.. PLoS Genet 2015 Jul;11(7):e1005427.
    pmc: PMC4512707pubmed: 26203908doi: 10.1371/journal.pgen.1005427google scholar: lookup
  21. Oeffner F, Fischer G, Happle R, König A, Betz RC, Bornholdt D, Neidel U, Boente Mdel C, Redler S, Romero-Gomez J, Salhi A, Vera-Casaño A, Weirich C, Grzeschik KH. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.. Am J Hum Genet 2009 Apr;84(4):459-67.
    pmc: PMC2667992pubmed: 19361614doi: 10.1016/j.ajhg.2009.03.014google scholar: lookup
  22. Oeffner F, Martinez F, Schaffer J, Salhi A, Monfort S, Oltra S, Neidel U, Bornholdt D, van Bon B, König A, Happle R, Grzeschik KH. Intronic mutations affecting splicing of MBTPS2 cause ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome.. Exp Dermatol 2011 May;20(5):447-9.
    pubmed: 21426410doi: 10.1111/j.1600-0625.2010.01238.xgoogle scholar: lookup
  23. Rausch T, Zichner T, Schlattl A, Stütz AM, Benes V, Korbel JO. DELLY: structural variant discovery by integrated paired-end and split-read analysis.. Bioinformatics 2012 Sep 15;28(18):i333-i339.
    pmc: PMC3436805pubmed: 22962449doi: 10.1093/bioinformatics/bts378google scholar: lookup
  24. Rawson RB, Zelenski NG, Nijhawan D, Ye J, Sakai J, Hasan MT, Chang TY, Brown MS, Goldstein JL. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs.. Mol Cell 1997 Dec;1(1):47-57.
    pubmed: 9659902doi: 10.1016/s1097-2765(00)80006-4google scholar: lookup
  25. Reish O, Gorlin RJ, Hordinsky M, Rest EB, Burke B, Berry SA. Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/BRESHECK): new X-linked syndrome?. Am J Med Genet 1997 Feb 11;68(4):386-90.
    pubmed: 9021007doi: 10.1002/(sici)1096-8628(19970211)68:4<386::aid-ajmg2>3.0.co;2-kgoogle scholar: lookup
  26. Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, Israël A, Heiss NS, Klauck SM, Kioschis P, Wiemann S, Poustka A, Esposito T, Bardaro T, Gianfrancesco F, Ciccodicola A, D'Urso M, Woffendin H, Jakins T, Donnai D, Stewart H, Kenwrick SJ, Aradhya S, Yamagata T, Levy M, Lewis RA, Nelson DL. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.. Nature 2000 May 25;405(6785):466-72.
    pubmed: 10839543doi: 10.1038/35013114google scholar: lookup
  27. Sponenberg D. P., 2009.  Equine color genetics, Ed. 3 Wiley-Blackwell, Ames.
  28. Sun BK, Tsao H. X-chromosome inactivation and skin disease.. J Invest Dermatol 2008 Dec;128(12):2753-9.
    pubmed: 18509358doi: 10.1038/jid.2008.145google scholar: lookup
  29. Towers RE, Murgiano L, Millar DS, Glen E, Topf A, Jagannathan V, Drögemüller C, Goodship JA, Clarke AJ, Leeb T. A nonsense mutation in the IKBKG gene in mares with incontinentia pigmenti.. PLoS One 2013;8(12):e81625.
    pmc: PMC3852476pubmed: 24324710doi: 10.1371/journal.pone.0081625google scholar: lookup
  30. Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF, Hakonarson H, Bucan M. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data.. Genome Res 2007 Nov;17(11):1665-74.
    pmc: PMC2045149pubmed: 17921354doi: 10.1101/gr.6861907google scholar: lookup
  31. Wang X, Reid Sutton V, Omar Peraza-Llanes J, Yu Z, Rosetta R, Kou YC, Eble TN, Patel A, Thaller C, Fang P, Van den Veyver IB. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia.. Nat Genet 2007 Jul;39(7):836-8.
    pubmed: 17546030doi: 10.1038/ng2057google scholar: lookup
  32. Zelenski NG, Rawson RB, Brown MS, Goldstein JL. Membrane topology of S2P, a protein required for intramembranous cleavage of sterol regulatory element-binding proteins.. J Biol Chem 1999 Jul 30;274(31):21973-80.
    pubmed: 10419520doi: 10.1074/jbc.274.31.21973google scholar: lookup

Citations

This article has been cited 6 times.
  1. Christen M, Booij-Vrieling H, Oksa-Minalto J, de Vries C, Kehl A, Jagannathan V, Leeb T. MIA3 Splice Defect in Cane Corso Dogs with Dental-Skeletal-Retinal Anomaly (DSRA). Genes (Basel) 2021 Sep 25;12(10).
    doi: 10.3390/genes12101497pubmed: 34680893google scholar: lookup
  2. Druet T, Legarra A. Theoretical and empirical comparisons of expected and realized relationships for the X-chromosome. Genet Sel Evol 2020 Aug 20;52(1):50.
    doi: 10.1186/s12711-020-00570-6pubmed: 32819272google scholar: lookup
  3. Bauer A, De Lucia M, Jagannathan V, Mezzalira G, Casal ML, Welle MM, Leeb T. A Large Deletion in the NSDHL Gene in Labrador Retrievers with a Congenital Cornification Disorder. G3 (Bethesda) 2017 Sep 7;7(9):3115-3121.
    doi: 10.1534/g3.117.1124pubmed: 28739597google scholar: lookup
  4. Bauer A, Hiemesch T, Jagannathan V, Neuditschko M, Bachmann I, Rieder S, Mikko S, Penedo MC, Tarasova N, Vitková M, Sirtori N, Roccabianca P, Leeb T, Welle MM. A Nonsense Variant in the ST14 Gene in Akhal-Teke Horses with Naked Foal Syndrome. G3 (Bethesda) 2017 Apr 3;7(4):1315-1321.
    doi: 10.1534/g3.117.039511pubmed: 28235824google scholar: lookup
  5. Durward-Akhurst SA, Marlowe JL, Schaefer RJ, Springer K, Grantham B, Carey WK, Bellone RR, Mickelson JR, McCue ME. Predicted genetic burden and frequency of phenotype-associated variants in the horse. Sci Rep 2024 Apr 10;14(1):8396.
    doi: 10.1038/s41598-024-57872-8pubmed: 38600096google scholar: lookup
  6. Rajawat D, Panigrahi M, Nayak SS, Bhushan B, Mishra BP, Dutt T. Dissecting the genomic regions of selection on the X chromosome in different cattle breeds. 3 Biotech 2024 Feb;14(2):50.
    doi: 10.1007/s13205-023-03905-4pubmed: 38268984google scholar: lookup
Subscribe to our newsletter
Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.