OMIA 001401-9823 : Waardenburg syndrome, type 2A in Sus scrofa
Hai et al. (2017): "performed ENU (ethylnitrosourea) mutagenesis that resulted in substituting a conserved lysine with a serine (p. L247S) in the DNA-binding domain of the MITF gene to generate a novel miniature pig model of WS2A." The affected animals from this study are genetically-modified organisms (GMO).Inheritance: Chen et al. (2016) summarise their inheritance studies as follows, where "albino" = pigs showing Waardenberg Syndrome 2A: "The deafness incidence rate in offspring of albino × albino mating was 100 %, whereas almost all offspring of normal × albino mating yielded normal hearing offspring. Moreover, there was no significant difference in the prevalence of deafness between males and females. These results implied an autosomal recessive inheritance pattern; to confirm this, 11 pairs of putative heterozygous boars and sows were selected from the normal herd according to the selection criteria of having produced at least one albino offspring. In total, 74 piglets from 11 litters of heterozygous × heterozygous matings were phenotyped to investigate the Mendelian segregation ratio; the results were 25 piglets with hearing loss and 49 piglets with normal hearing. Results of χ2 goodness-of-fit test indicated that the segregating ratio of the hearing loss trait was 3:1 (P < 0.01; . . . ), confirming that the trait’s inheritance mode was autosomal recessive." Mapping: Chen et al. (2016) "mapped the causative mutant gene of hearing loss to a 763 kb interval (SSC 13: 56,170,062 to 56,933,573)" Molecular basis: Noting that MITF is the only annotated gene located in the locational candidate region (see Mapping section), and from the results of several functional assays, Chen et al. (2016) eventually concluded that the likely causal variant is a 14bp insertion (g.56482632_56482633insTTTAGTTTAAAAAA) in the upstream non-regulatory region of MITF, which actually created a novel cis-regulatory element (CRE) which, when bound by SOX protein, prevents the transcription of the M isoform of MITF peptide. To the authors' knowledge, "this study provides the first evidence of a de novo CRE in mammals that produces a systemic functional effect." Clinical features: Chen et al. (2016): "Results from auditory brainstem response (ABR) tests show that the albino pigs produced no recognizable waveforms up to 100 dB sound pressure level (SPL) stimuli in the range from 4–32 kHz, whereas normal pigs produced ABR thresholds at 5–10 dB SPL . . . . Loss of hair cells and stereocilia bundles were observed in the cochleae of the albino pigs by scanning electron microscopy . . . . Because the hearing loss observed in human cases of WS2 is attributed to abnormal cochlear stria vascularis (SV) . . . , the morphology of SV was examined in our study’s albino pigs using light microscopy and transmission electron microscopy (TEM). . . . the albino pigs lacked intermediate cells and had thinner SVs, consisting of two layers of cells only. Because the major functions of the SV are secretion of potassium ions and production of endolymphatic potential (EP), we recorded EPs and measured the [K+] in the scala media of the cochlea. The EP and [K+] were significantly lower than those of normal pigs (P < 0.001, Student’s t-test; . . . ). Since EP and high [K+] in the endolymph are reportedly the driving force for mechanotransduction in cochlear hair cells . . . , a reduction in EP can lead to profound hearing loss. All these phenotypes were tested at postnatal day 13. Thus, these results confirmed the phenotype of profound hearing loss related to cochlear morphology defects in our study’s albino pigs." Breed: Rongchang. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|MITF||microphthalmia-associated transcription factor||Sus scrofa||13||NC_010455.5 (51177356..51422096)||MITF||Homologene, Ensembl, NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
|Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|Rongchang||Waardenburg syndrome, type 2A||MITF||insertion, small (<=20)||Sscrofa11.1||13||g.51377987_51377988insTTTAGTTTAAAAAA||a 14 bp insertion "in the non-regulatory region of the melanocyte-specific promoter of microphthalmia-associated transcription factor (MITF) gene generated a novel silencer"||2016||27349893|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2021||Yao, J., Wang, Y., Cao, C., Song, R., Bi, D., Zhang, H., Li, Y., Qin, G., Hou, N., Zhang, N., Zhang, J., Guo, W., Yang, S., Wang, Y., Zhao, J. :|
|CRISPR/Cas9-mediated correction of MITF homozygous point mutation in a Waardenburg syndrome 2A pig model Mol Ther Nucleic Acids 24:986-999, 2021. Pubmed reference: 34094716. DOI: 10.1016/j.omtn.2021.04.009.|
|Zhang, J., Khazalwa, E.M., Abkallo, H.M., Zhou, Y., Nie, X., Ruan, J., Zhao, C., Wang, J., Xu, J., Li, X., Zhao, S., Zuo, E., Steinaa, L., Xie, S. :|
|The advancements, challenges, and future implications of the CRISPR/Cas9 system in swine research. J Genet Genomics 48:347-360, 2021. Pubmed reference: 34144928. DOI: 10.1016/j.jgg.2021.03.015.|
|2017||Hai, T., Guo, W., Yao, J., Cao, C., Luo, A., Qi, M., Wang, X., Wang, X., Huang, J., Zhang, Y., Zhang, H., Wang, D., Shang, H., Hong, Q., Zhang, R., Jia, Q., Zheng, Q., Qin, G., Li, Y., Zhang, T., Jin, W., Chen, Z.Y., Wang, H., Zhou, Q., Meng, A., Wei, H., Yang, S., Zhao, J. :|
|Creation of miniature pig model of human Waardenburg syndrome type 2A by ENU mutagenesis. Hum Genet 136:1463-1475, 2017. Pubmed reference: 29094203. DOI: 10.1007/s00439-017-1851-2.|
|2016||Chen, L., Guo, W., Ren, L., Yang, M., Zhao, Y., Guo, Z., Yi, H., Li, M., Hu, Y., Long, X., Sun, B., Li, J., Zhai, S., Zhang, T., Tian, S., Meng, Q., Yu, N., Zhu, D., Tang, G., Tang, Q., Ren, L., Liu, K., Zhang, S., Che, T., Yu, Z., Wu, N., Jing, L., Zhang, R., Cong, T., Chen, S., Zhao, Y., Zhang, Y., Bai, X., Guo, Y., Zhao, L., Zhang, F., Zhao, H., Zhang, L., Hou, Z., Zhao, J., Li, J., Zhang, L., Sun, W., Zou, X., Wang, T., Ge, L., Liu, Z., Hu, X., Wang, J., Yang, S., Li, N. :|
|A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs. BMC Biol 14:52, 2016. Pubmed reference: 27349893. DOI: 10.1186/s12915-016-0273-2.|
|2012||Chen, L., Guo, W., Wang, J., Wang, S., Hu, X., Li, N. :|
|Hereditary sensorineural hearing loss in Chinese Rongchang pigs result from promoter mutations in Mitf. Proceedings of the 33rd Conference of the International Society of Animal Genetics :Abstract P2009, 2012.|
- Created by Frank Nicholas on 18 Oct 2017
- Changed by Frank Nicholas on 18 Oct 2017
- Changed by Imke Tammen2 on 25 Jun 2021