1. ^*Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
2. ^†Department of Dermatology, Izumi Municipal Hospital, Izumi, Japan
3. ^‡Department of Dermatology, Saiseikai Tondabayashi Hospital, Tondabayashi, Japan
4. ^§Genetics and Molecular Medicine Unit, University of Florence, Florence, Italy
5. ^¶Départment de Biochimie, Université de la Méditerranée, Marseille, France
6. ^#Department of Dermatology, St Marianna Medical University School of Medicine, Kawasaki, Japan
7. ^**Clinical and Molecular Genetics Unit, Institute of Child Health, London, UK
8. ^††Department of Dermatology, Yamanashi Prefectural Central Hospital, Kofu, Japan
9. ^‡‡Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Japan
10. ^§§Department of Dermatology, Northwestern University, Chicago, Illinois, USA
11. ^¶¶Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
12. ^##Spectrum Health, Grand Rapids, Michigan, USA
13. ^***International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
14. ^†††Genetics-Biology Institute, University of Antiquia, Medellìn, Colombia
15. ^‡‡‡Regional Genetics Center Children's Hospital, Columbus, Ohio, USA

Correspondence: Kazuyoshi Fukai MD, Department of Dermatology, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi Abenoku, Osaka 545-8585, Japan. Email: fukai@msic.med.osaka-cu.ac.jp

Received 17 October 2004; Revised 19 November 2004; Accepted 23 November 2004.

Abstract

Piebaldism is an autosomal dominant disorder, characterized by congenital leukoderma typically on the abdomen, knees, and forehead. Mice models for human piebaldism are the W dominant white spotting, the steel mice and the mice that are mutated for the slug gene. Human genes for these mice models were investigated in this study. Genomic DNAs of peripheral leukocytes were prepared from twenty-two patients with piebaldism. PCR-direct sequencing or screening by SSCP and subsequent sequencing of all of the exons and flanking introns of KIT, SCF (stem cell factor), and SLUG genes disclosed six pathological mutations only in KIT. Among them five were novel: 358delG, IVS3-2A>G, Q346X, H650L, and D792Y. His650 is located in the strand connecting the helix C and the downstream -sheet of the N-lobe of the active KIT kinase domain, the crystal fine structure of which was determined recently. Asp792 is situated in the center of the kinase active site of interdomain cleft between the N-lobe and the C-lobe. No pathological mutations were found in SCF or SLUG in our screening system. Analysis of mutations in the KIT kinase domain may offer an insight into the detailed functional role of this fascinating protein.