Abstract Complementary and genomic DNAs isolated from the fibroblasts of 10 Japanese (7 late infantile, 2 juve- nile, and 1 adult form of the disease) and one Caucasian pa- tient with Niemann-Pick disease type C were analyzed for mutations in the NPC1 gene. Fourteen novel mutations were found including small deletions and point mutations. A one-base deletion and a point mutation caused splicing errors. The mutations were not clustered in any particular region of the gene and were found both in and out of the transmembrane domains. Three patients were homozygous, five were compound heterozygous, and the remaining three were suspected of being compound hetrozygous with an un- known error in one of their NPC1 alleles. Of the 14 muta- tions, the G1553A substitution that caused a splicing error of exon 9 appeared to be relatively common in Japanese patients, because two patients were homozygous and one patient was compound heterozygous for this mutation. Introduction Niemann-Pick disease type C (NPC; MIM no. 257220) is an autosomal recessive disorder characterized by progres- sive neurological dysfunctions and hepatosplenomegaly. Cultured fibroblasts from patients with NPC show re- tarded esterification of low density lipoprotein (LDL)-de- rived cholesterol and lysosomal accumulation of free cho- lesterol, suggesting a defect in the intracellular transport of LDL-derived cholesterol (Pentchev et al. 1995). De- pending on clinical onset and phenotypes, NPC patients can be classified into four groups, viz., those having se- vere infantile, late infantile, juvenile, or adult forms of the disease (Pentchev et al. 1995; Vanier and Suzuki 1998). There is little correlation between the abilities of skin fi- broblasts to esterify LDL-derived cholesterol and the severity of the disease course (Vanier et al. 1991a, 1991b). The chromosomal location of the gene responsible for NPC was first mapped to either 18pter-p11.3 or 18q21.3- qter by the microcell hybridization technique (Kurimasa et al. 1993) and further refined to 18q11-q12 by a linkage study (Carstea et al. 1994). Cell hybridization analysis has demonstrated the presence of at least two genetically het- erogeneous subgroups in this disease (Steinberg et al. 1994; Vanier et al. 1996). The major group (more than 90% of NPC patients) has been linked to chromosome 18 (Vanier et al. 1996). Carstea et al. (1997) have identified the NPC1 cDNA responsible for the major group of NPC. It encodes 1278 Toshiyuki Yamamoto · Eiji Nanba · Haruaki Ninomiya · Katsumi Higaki · Miyako Taniguchi · Haidi Zhang · Shinjiro Akaboshi · Yasuhiro Watanabe · Takao Takeshima · Koji Inui · Shintaro Okada · Akemi Tanaka · Norio Sakuragawa · Gilles Millat · Marie T. Vanier · Jill A. Morris · Peter G. Pentchev · Kousaku Ohno NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C Hum Genet (1999) 105 : 10–16 © Springer-Verlag 1999 Digital Object Identifier (DOI) 10.1007/s004399900059 Received: 4 January 1999 / Accepted: 3 April 1999 / Published online: 8 July 1999 ORIGINAL INVESTIGATION T. Yamamoto (✉) · E. Nanba Gene Research Center, Tottori University, 86 Nishi-machi, Yonago 683–8503, Japan e-mail: tyamamot@grape.med.tottori-u.ac.jp, Tel.: +81 859 34 8283, Fax: +81 859 34 8284 H. Ninomiya · K. Higaki · M. Taniguchi · H. Zhang · K. Ohno Department of Neurobiology, School of Life Sciences, Faculty of Medicine, Tottori University, Yonago, Japan S. Akaboshi Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago, Japan Y. Watanabe · T. Takeshima Division of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago, Japan K. Inui · S. Okada Department of Pediatrics, Osaka University Medical School, Osaka, Japan A. Tanaka Department of Pediatrics, Osaka City University School of Medicine, Osaka, Japan N. Sakuragawa Department of Inherited Metabolic Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan G. Millat · M. T. Vanier Department of Biochemistry and INSERM U 189, Lyon-Sud Medical School, Lyon, France J. A. Morris · P. G. Pentchev National Institute of Neurological Disorders and Stroke, National Institute of Health (NIH), Bethesda, USA