Introduction
Piebaldism (MIM #172800) is a rare autosomal dominant disorder
characterized by a congenital white forelock and leukoderma on the
frontal scalp, forehead, ventral trunk, and extremities. This phenotype
was induced by the abnormal migration of neural crest derived
melanoblasts to the skin during embryogenesis or the local postnatal
migration of skin melanoblasts and melanocytes(Alexeev & Yoon, 2006;
Bondanza et al., 2007; Grichnik, 2006).
Various “loss-of-function”
mutations in c-KIT have been demonstrated in about 75% of the
patients with piebaldism(Ezoe et al., 1995; Murakami et al., 2004;
Murakami et al., 2005). Also, a satisfactory correlation has been
described between the mutant genotype and clinical phenotypes: missense
mutations in the extracellular ligand-binding domain and nonsense
mutations preserved approximately 50% of the c-KIT function and
induced mild piebaldism by haploinsufficiency; mutations in the tyrosine
kinase domain preserved approximately 25% of the c-KIT function
and induced severe piebaldism through a dominant-negative effect(Oiso,
Fukai, Kawada, & Suzuki, 2013; Spritz, 1994; Ward, Moss, & Sanders,
1995).
Interestingly, piebaldism combined with congenital deafness was firstly
reported in two Hopi Indian brothers in Arizona(Woolf, 1965). Until
1998, Spritz et al. firstly described the pathogenicity of heterozygous
c-KIT (p.R796G) in piebaldism with congenital deafness(Spritz &
Beighton, 1998). Recently, the homozygous deletion of exons 20 and 21 inc-KIT was reported to induce piebaldism and deafness in
humans(Kilsby et al., 2013), and the heterozygous mutation of A608D was
found in one adult patient with non-hereditary unilateral
deafness(Hamadah et al., 2019). Furthermore, several KIT mutations
(KITW-V , KIT Wads , and
KITF856S) have been identified in mice with
hypopigmentation and hearing loss(Hoshino et al., 2000; J. CABLE, 1994;
Ruan, Zhang, & Gao, 2005). Nevertheless,
the low and irregular coincidence
of piebaldism with hearing loss seemed to be an expanded and occasional
manifestation of c-KIT mutations.
Thus, piebaldism was speculated as
an inherited condition in an intermediate rather than a dominant
manner(Hamadah et al., 2019; Spritz & Beighton, 1998).
In pigs, c-KIT is highly related with the dominant white color
phenotype by two mutations: the copy number variations of the entire
gene (~450 kbp) and a G to A substitution in the first
nucleotide of intron 17(Giuffra et al., 2002; Johansson, Pielberg,
Andersson, & Edfors-Lilja, 2005; Pielberg, Olsson, Syvanen, &
Andersson, 2002). To date, six c-KIT alleles have been reported
in pigs: i , the recessive allele in wild boar;IBe , the dominant allele for the belt phenotype
in Hampshire pigs; IP , the half dominant allele
for the patch phenotype in Pietrain; I(I1 , I2 , orI3 ), the completely dominant allele for white
color in Landrace and large white pigs. The polymorphisms in the
c-KIT sequence could discriminate the European from the Asian
groups, the two main clusters produced during the domestication
history(Niu, Shi, Xie, Liu, & Zhong, 2018). On the other hand, pigs
exhibit more similar audiological characteristics to humans than
rodents, including the cochlear structure, the range of audible
frequency, and sensitivity to sound(Chen et al., 2016; Guo et al., 2015;
Hai, Guo, et al., 2017), making it more advantageous in the research and
treatment of hearing loss.
Previously, we reported the first large-scale ENU-mediated mutagenesis
program in pigs in the world using Chinese Bama miniature pig and
identified 36 dominant and 91 recessive novel strains(Hai, Cao, et al.,
2017). One of the dominant inherited strain exhibited a severe phenotype
of piebaldism and congenital profound hearing loss.
The
genome-wide association study (GWAS)
and linkage analysis identified a de novo mutation inc-KIT (c. 2430T>A), which induced the missense
mutation of Asp810Glu in c-KIT protein. Then, we described theIBe genotype of c-KIT in wild-type Bama
pigs. In addition, the pathological results revealed the collapse of
Reissner’s membrane and the absence of hair cells in the mutant inner
ear. Finally, we reanalyzed the mutations in c-KIT gene to
provide new clues for understanding the etiology and development of
piebaldism with hearing loss.