Hypopigmentation/Deafness) J Med Genet: First Published As 10.1136/Jmg.37.6.446 on 1 June 2000
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446 J Med Genet 2000;37:446–448 Tietz syndrome (hypopigmentation/deafness) J Med Genet: first published as 10.1136/jmg.37.6.446 on 1 June 2000. Downloaded from caused by mutation of MITF Shelley D Smith, Philip M Kelley, Judith B Kenyon, Denise Hoover Abstract In 1963, Tietz1 described an autosomal domi- Patients with Tietz syndrome have con- nant syndrome of hypopigmentation and deaf- genital profound deafness and generalised ness in a large three generation family (MIM hypopigmentation, inherited in a fully 103500). There were no further reports of this penetrant autosomal dominant fashion. syndrome, and Reed et al2 suggested the coseg- The pigmentary features and complete regation of the two features had been coinci- dental in that family. Center for Hereditary penetrance make this syndrome distinct Communication among syndromes with pigmentary We were contacted by a family who sus- Disorders, Boys Town anomalies and deafness, which character- pected they had a unique form of deafness, and National Research istically have patchy depigmentation and they wanted to know if there were any other Hospital, 555 North variable penetrance. Only one family has families with similar findings. In particular, 30th Street, Omaha, they wanted to locate a branch of their family NE 68131, USA been reported with the exact features S D Smith* described in the original report of this which had become separated in the mid 1800s. P M Kelley syndrome. This family was reascertained This family has traced their ancestry in the J B Kenyon* and a missense mutation was found in the USA to North Carolina in the mid 1700s and D Hoover* basic region of the MITF gene in family believe the founder in the USA emigrated from Derry, Ireland. They described themselves as Correspondence to: members with Tietz syndrome. Mutations having profound congenital deafness along Dr Smith, [email protected] in other regions of this gene have been with blonde hair and white eyelashes and found to produce Waardenburg syndrome *Present address: Center for eyebrows, transmitted through at least seven Human Molecular Genetics, type 2 (WS2), which also includes pigmen- generations. Review of published reports and Munroe Meyer Institute, tary changes and hearing loss, but in con- 985455 University of comparison with the pedigree information Nebraska Medical Center, trast to Tietz syndrome, depigmentation provided by the family indicated that this was a Omaha, NE 68198-5455, is patchy and hearing loss is variable in USA separate branch of the same family reported by WS2. Tietz1 (fig 1). (J Med Genet 2000;37:446–448) Revised version received Eleven family members were personally 17 December 1999 Accepted for publication 25 Keywords: Tietz syndrome; Waardenburg syndrome; examined and audiograms were obtained on all http://jmg.bmj.com/ January 2000 deafness; MITF of them. Six of these 11 family members had more extensive tests at Boys Town National I ?? II on September 24, 2021 by guest. Protected copyright. III IV V 3 4 4 4 3 2 3 4 3 4 5 3 4 3 2 1 5 3 5 5 2 3 2 3 1 2 1 3 4 3 VI 1 4 3 4 3 4 1 2 3 4 1 1 4 4 1 2 2 5 2 5 2 3 5 1 2 3 5 5 5 3 4 2 2 2 1 1 1 3 1 2 1 1 2 2 3 3 2 2 VII 2 3 2 4 1 3 3 4 2 4 1 1 2 1 3 5 5 2 5 2 3 4 2 3 2 3 2 2 1 3 2 3 2 Figure 1 Pedigree of family 815 showing segregation of the hypopigmentation/deafness through seven generations according to their genealogical records. Filled symbols indicate hypopigmentation and deafness, while half filled symbols indicate isolated deafness. Family members who participated in the 1963 report by Tietz1 are indicated in the box. Haplotypes are shown for markers D3S1285, D3S1566, and D3S1271. MITF mutation causing Tietz syndrome 447 Research Hospital, including vestibular assess- the woman had generalised depigmentation ment, ophthalmological examination with fun- with reddish freckles and reddish hair which J Med Genet: first published as 10.1136/jmg.37.6.446 on 1 June 2000. Downloaded from dus photography, and physical examination for became grey-blonde at the age of 18. At 18 dysmorphology. Four family members who months of age, her son had auburn hair. Both could not be seen by the authors provided had lack of retinal pigmentation. Although the photographs, audiograms, and medical degree of hypopigmentation is not identical to records. Photographs were also available for the phenotype in the present family, this members of previous generations. phenotype was felt by the authors to be closest With signed consent, blood was obtained to Tietz syndrome. The finding of an MITF from 19 family members for linkage and muta- mutation in our family would confirm that tion analyses. Two point linkage analysis was diagnosis. done using the LINKAGE analysis program Waardenburg syndrome type 2 (WS2) is with the trait locus treated as a fully penetrant characterised by sensorineural hearing loss of autosomal dominant condition with no spo- varying degrees in about 70% of gene radic cases.3 This produced a maximum lod carriers.78 Vestibular dysfunction has been score of 3.612 at zero recombination for the reported in WS2, along with inner ear malfor- marker D3S1566, which is located at 3p12.3. mations particularly involving the semicircular The gene MITF (microphthalmia associated canals.9 Depigmentation is patchy, but most transcription factor) is known to be in this typically includes a white forelock, early region, and mutations of this gene can produce greying, and heterochromia irides. There is the Waardenburg syndrome type 2 phenotype.4 genetic heterogeneity within WS2, in that Heteroduplex analysis was used for mutation approximately 15% of families with WS2 have detection in MITF, with direct sequencing to mutations in the MITF gene.7 define the mutations. This detected sequence Although caused by mutation in the same variations in aVected subjects in intron 5 and gene which can cause WS2, the Tietz syn- exon 6. The PCR amplimer from exon 5 and drome phenotype is diVerent in several re- adjacent intron sequence included a change of spects. Deafness is always congenital and a C to G at nucleotide +9 in the 5' end of intron profound and is completely penetrant, there is 5. This places the mutation out of the 5' splice no patchiness to the pigmentation, and no het- consensus region, so that it should not have an erochromia. Features similar to WS2 include eVect on the normal maturation of the mRNA. fundus hypopigmentation, possible vestibular In exon 6, aVected subjects were heterozygous dysfunction, and lack of facial dysmorphology. foraGtoCpoint mutation at nucleotide 600. MITF is a transcription factor of the basic This would result in substitution of lysine for helix-loop-helix zipper family of proteins,10 and asparagine (Asn210Lys) in the mutant protein. appears to be necessary for the development These variations were not found in the and survival of melanocytes, osteoclasts, and unaVected subjects, nor in 96 unrelated control mast cells.10–12 In these transcription factors, the samples. basic portion of the molecule is involved in http://jmg.bmj.com/ According to family report, aVected family binding specific DNA promoter sequences, members with Tietz syndrome are born “snow and the helix-loop-helix and zipper motifs sta- white”. They gradually gain some pigmenta- bilise dimerisation with itself or other proteins tion and have fair skin and blonde to white hair in the same subfamily. The change in exon 6 of as adults with white eyebrows and eyelashes. MITF in this family would produce a substitu- They may have reddish freckles and some sub- tion of lysine for asparagine in the basic region jects reported they can even tan slightly with of the transcribed protein. Asparagine is a neu- very careful exposure to sun. tral, polar amino acid, while lysine is basic. on September 24, 2021 by guest. Protected copyright. All aVected subjects have blue eyes and oph- Since the basic region of the MITF protein is thalmological examination showed hypopig- important for binding to the major groove of mented fundi, but there is no nystagmus or DNA, these changes in size and charge would other visual problems and no heterochromia be predicted to interfere with that function. In irides. Hearing loss is always bilateral, congeni- the heterozygote, the mutant MITF protein tal, sensorineural, and profound, and aVected would be expected to dimerise eVectively with subjects communicate manually. Vestibular itself or with a normal allele product; however, studies showed a slight low frequency phase the resulting dimer would bind to DNA poorly, lead with rotary chair testing on all four tested so the overall eVect of the mutation should be subjects. This suggests vestibular dysfunction, dominant negative. In contrast, mutations of but caloric testing to delineate the nature of the MITF that produce WS2 either truncate the dysfunction was not performed. Medical product or aVect its dimerisation by disrupting records from VI.7 indicated that a CT scan of the helix-loop-helix or zipper motifs. As shown the temporal bones showed a fistula of the lat- by in vitro studies of WS2 mutations in the eral semicircular canal; however, he was a heterozygous state, these mutations do not scuba diver, so it is not known if this was interfere with the product of the normal allele, related to barotrauma. which is still free to form a normally function- Tassabehji et al5 and Amiel et al6 have ing protein.12 Thus, the mechanism for WS2 described a mother and son who also had a appears to be through haploinsuYciency.61213 mutation in the basic region of MITF at the MITF is homologous to the Mitf (mi) gene in nearby amino acid position 217.