Mutations in the Paired Domain of the Human PAX3 Gene Cause Klein-Waardenburg Syndrome (WS-III) As Well As Waardenburg Syndrome Type I (WS-I)

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 1993 Mar 1

PMID 8447316

Citations 66

Authors

C F Hoth

A Milunsky

N Lipsky

R Sheffer

S K Clarren

C T Baldwin

Affiliations

Soon will be listed here.

Abstract

Waardenburg syndrome type I (WS-I) is an autosomal dominant disorder characterized by sensorineural hearing loss, dystopia canthorum, pigmentary disturbances, and other developmental defects. Klein-Waardenburg syndrome (WS-III) is a disorder with many of the same characteristics as WS-I and includes musculoskeletal abnormalities. We have recently reported the identification and characterization of one of the first gene defects, in the human PAX3 gene, which causes WS-I. PAX3 is a DNA-binding protein that contains a structural motif known as the paired domain and is believed to regulate the expression of other genes. In this report we describe two new mutations, in the human PAX3 gene, that are associated with WS. One mutation was found in a family with WS-I, while the other mutation was found in a family with WS-III. Both mutations were in the highly conserved paired domain of the human PAX3 gene and are similar to other mutations that cause WS. The results indicate that mutations in the PAX3 gene can cause both WS-I and WS-III.

Citing Articles

Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health.

Mkaouar R, Riahi Z, Marrakchi J, Mezzi N, Romdhane L, Boujemaa M Front Genet. 2024; 15:1384094.

PMID: 38711914 PMC: 11072975. DOI: 10.3389/fgene.2024.1384094.

The PAX Genes: Roles in Development, Cancer, and Other Diseases.

Shaw T, Barr F, Uren A Cancers (Basel). 2024; 16(5).

PMID: 38473380 PMC: 10931086. DOI: 10.3390/cancers16051022.

A novel frameshift mutation in SOX10 gene induced Waardenburg syndrome type II.

Ma X, Zhao L, Li L, Li X, Ding C, Ma J Mol Genet Genomic Med. 2024; 12(3):e2296.

PMID: 38419387 PMC: 10958176. DOI: 10.1002/mgg3.2296.

Waardenburg Syndrome: The Contribution of Next-Generation Sequencing to the Identification of Novel Causative Variants.

Bertani-Torres W, Lezirovitz K, Alencar-Coutinho D, Pardono E, da Costa S, Antunes L Audiol Res. 2024; 14(1):9-25.

PMID: 38391765 PMC: 10886116. DOI: 10.3390/audiolres14010002.

Loss of Pax3 causes reduction of melanocytes in the developing mouse cochlea.

Udagawa T, Takahashi E, Tatsumi N, Mutai H, Saijo H, Kondo Y Sci Rep. 2024; 14(1):2210.

PMID: 38278860 PMC: 10817906. DOI: 10.1038/s41598-024-52629-9.

References

Baldwin C, Hoth C, AMOS J, Milunsky A . An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. Nature. 1992; 355(6361):637-8. DOI: 10.1038/355637a0. View

. Waardenburg I syndrome: a clinical and genetic study of two large Brazilian kindreds, and literature review. Am J Med Genet. 1991; 40(1):65-74. DOI: 10.1002/ajmg.1320400113. View

Jordan T, Hanson I, Zaletayev D, Hodgson S, Prosser J, Seawright A . The human PAX6 gene is mutated in two patients with aniridia. Nat Genet. 1992; 1(5):328-32. DOI: 10.1038/ng0892-328. View

Morell R, Friedman T, Moeljopawiro S, Hartono , Soewito , Asher Jr J . A frameshift mutation in the HuP2 paired domain of the probable human homolog of murine Pax-3 is responsible for Waardenburg syndrome type 1 in an Indonesian family. Hum Mol Genet. 1992; 1(4):243-7. DOI: 10.1093/hmg/1.4.243. View

Steel K, Smith R . Normal hearing in Splotch (Sp/+), the mouse homologue of Waardenburg syndrome type 1. Nat Genet. 1992; 2(1):75-9. DOI: 10.1038/ng0992-75. View

Clarren S, Steege T . Waardenburg syndrome associated with meningomyelocele. Am J Med Genet. 1992; 42(1):135-6. DOI: 10.1002/ajmg.1320420127. View

WAARDENBURG P . A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J Hum Genet. 1951; 3(3):195-253. PMC: 1716407. View

Hageman M, DELLEMAN J . Heterogeneity in Waardenburg syndrome. Am J Hum Genet. 1977; 29(5):468-85. PMC: 1685402. View

SANGER F, Nicklen S, Coulson A . DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977; 74(12):5463-7. PMC: 431765. DOI: 10.1073/pnas.74.12.5463. View

10.

Garnier J, Osguthorpe D, Robson B . Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol. 1978; 120(1):97-120. DOI: 10.1016/0022-2836(78)90297-8. View

11.

Bopp D, Burri M, Baumgartner S, Frigerio G, Noll M . Conservation of a large protein domain in the segmentation gene paired and in functionally related genes of Drosophila. Cell. 1986; 47(6):1033-40. DOI: 10.1016/0092-8674(86)90818-4. View

12.

Chalepakis G, Fritsch R, Fickenscher H, Deutsch U, Goulding M, Gruss P . The molecular basis of the undulated/Pax-1 mutation. Cell. 1991; 66(5):873-84. DOI: 10.1016/0092-8674(91)90434-z. View

13.

Epstein D, Vekemans M, Gros P . Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell. 1991; 67(4):767-74. DOI: 10.1016/0092-8674(91)90071-6. View

14.

Hill R, Favor J, Hogan B, Ton C, Saunders G, Hanson I . Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature. 1991; 354(6354):522-5. DOI: 10.1038/354522a0. View

15.

Walther C, Guenet J, Simon D, Deutsch U, Jostes B, Goulding M . Pax: a murine multigene family of paired box-containing genes. Genomics. 1991; 11(2):424-34. DOI: 10.1016/0888-7543(91)90151-4. View

16.

Sheffer R, Zlotogora J . Autosomal dominant inheritance of Klein-Waardenburg syndrome. Am J Med Genet. 1992; 42(3):320-2. DOI: 10.1002/ajmg.1320420312. View

17.

Tassabehji M, Read A, Newton V, Harris R, Balling R, Gruss P . Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature. 1992; 355(6361):635-6. DOI: 10.1038/355635a0. View

18.

Baumgartner S, Bopp D, Burri M, Noll M . Structure of two genes at the gooseberry locus related to the paired gene and their spatial expression during Drosophila embryogenesis. Genes Dev. 1987; 1(10):1247-67. DOI: 10.1101/gad.1.10.1247. View

19.

Saiki R, Gelfand D, Stoffel S, Scharf S, Higuchi R, Horn G . Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988; 239(4839):487-91. DOI: 10.1126/science.2448875. View

20.

Schleif R . DNA binding by proteins. Science. 1988; 241(4870):1182-7. DOI: 10.1126/science.2842864. View