In a family with partial albinism and sensorineural deafness (TADS; 103500), Tassabehji et al. (1995) identified the exact equivalent of the mouse microphthalmia mutation, namely a deletion of 1 of a run of 4 arginines in the basic domain. Following the mouse precedent, they labeled this mutation R217del, although from the DNA and protein sequences one could not say which of the 4 arginines was deleted. Amiel et al. (1998) noted that although the affected mother and son fulfilled diagnostic criteria for Waardenburg syndrome type 2 (see 193510), they more closely resembled the family reported by Tietz (1963).
In a 24-year-old woman with Tietz syndrome, Izumi et al. (2008) identified heterozygosity for the R217del mutation in the MITF gene. The authors noted that dimerization between mutant and wildtype protein would reduce the number of intact wildtype dimers with access to the nucleus to 25% of normal. Histologic examination of skin biopsy specimens revealed the presence of melanocytes, suggesting that the migration of melanocyte stem cells from the neural crest to the epidermal layer occurred normally. In the hypopigmented regions, however, a reduction in the number of melanosomes in keratinocytes adjacent to the melanocytes suggested a disruption in the transfer of melanosomes from the melanocytes to the keratinocytes; and in the hyperpigmented regions, an increase in the number of melanosomes in the keratinocytes adjacent to HMB45-positive melanocytes pointed to a high level of melanogenesis.
In a 5-year-old boy with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; 617306), George et al. (2016) identified compound heterozygosity for mutations in the MITF gene: the first was a 3-bp deletion (c.952_954delAGA), which they stated corresponded to Arg318del in the MITF-A isoform and to Arg217del in the MITF-M isoform; the second was a c.921G-C transversion, resulting in a lys307-to-asn (K307N; 156845.0010) substitution in isoform MITF-A. The proband's parents and 1 brother, who exhibited features of WS2A, were each heterozygous for 1 of the mutations. The K307N mutation was not found in the 1000 Genomes Project, dbSNP, Exome Variant Server, or ExAC databases. Functional analysis showed that, unlike wildtype MITF, the R318del mutant did not migrate to the nucleus in transfected HEK293 cells or bind consensus M-box or E-box DNA sequences in vitro; in addition, this allele did not activate the tyrosinase (TYR; 606933) promoter or repress the FGF19 (603891) promoter in dual luciferase reporter assays. In comparison, the K307N allele was distributed equally between the nucleus and the cytoplasm and exhibited approximately 20% of the DNA-binding capability of wildtype MITF, but had significant transcriptional regulatory potential on TYR and FGF19 promoters. Coexpression of R318del and K307N in HEK293 cells resulted in migration of only 30% of MITF into the nucleus, whereas coexpression of mutant with wildtype protein resulted in 36% or 81% migration, respectively. DNA binding of co-in-vitro-translated R318del and K307N was less than 20% of that of wildtype MITF for consensus E-box and M-box elements; wildtype with R318del resulted in approximately 50% reduction of DNA binding, whereas wildtype with K307N bound both consensus elements better than wildtype. Transcriptional activation of the TYRP1 (115501) promoter was reduced more dramatically when increasing amounts of R318del were coexpressed with K307N than with wildtype.
