A Physical and Transcript Map of the M COLN1 Gene Region on Human Chromosome 19p13.3–p13.2 James S. Acierno, jr.,* , † John C. Kennedy,* , † John L. Falardeau,* , † Maire Leyne,* , † Matthew C. Bromley,* , † Matthew W. Colman,* , † Mei Sun,‡ Catherine Bove,† Linda K. Ashworth,§ Lisa H. Chadwick,* , † Taryn Schiripo,* , † Sue Ma,* , † Ehud Goldin,‡ Raphael Schiffmann,‡ and Susan A. Slaugenhaupt * , † ,1 * Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts 02115; †Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129; ‡Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; and §Human Genome Center, Lawrence Livermore National Laboratory, Livermore, California 94550 Received December 6, 2000; accepted February 12, 2001 Mutations in MCOLN1 have been found to cause mu- colipidosis type IV (MLIV; MIM 252650), a rare autoso- mal recessive lysosomal storage disorder found pri- marily in the Ashkenazi Jewish population. As a part of the successful cloning of MCOLN1, we constructed a 1.4-Mb physical map containing 14 BACs and 4 cos- mids that encompasses the region surrounding MCOLN1 on human chromosome 19p13.3–p13.2—a re- gion to which linkage or association has been reported for multiple diseases. Here we detail the precise phys- ical mapping of 28 expressed sequence tags that rep- resent unique UniGene clusters, of which 15 are known genes. We present a detailed transcript map of the MCOLN1 gene region that includes the genes KIAA0521, neuropathy target esterase (NTE), a novel zinc finger gene, and two novel transcripts in addition to MCOLN1. We also report the identification of eight new polymorphic markers between D19S406 and D19S912, which allowed us to pinpoint the location of MCOLN1 by haplotype analysis and which will facili- tate future fine-mapping in this region. Additionally, we briefly describe the correlation between the ob- served haplotypes and the mutations found in MCOLN1. The complete 14-marker haplotypes of non- Jewish disease chromosomes, which are crucial for the genetic diagnosis of MLIV in the non-Jewish pop- ulation, are presented here for the first time. © 2001 Academic Press INTRODUCTION Mucolipidosis type IV (MLIV; MIM 252650) is an autosomal recessive disease that usually presents in the first year of life with corneal clouding, delayed psychomotor development, and mental retardation (Amir et al., 1987). Although most patients have been of Ashkenazi Jewish (AJ) descent, several cases have been reported in non-Jewish (NJ) patients (Goutieres et al., 1979; Riedel et al., 1985). Previously, we linked this disease to a region on chromosome 19p13.3–p13.2, a locus now designated MCOLN1 (GenBank Accession No. AF287269). A strong founder effect was observed, and subsequent haplotype analysis allowed the candi- date interval to be narrowed to a 1.2-cM region be- tween the markers D19S406 and D19S912 (Slaugen- haupt et al., 1999). We have recently demonstrated that mutations in MCOLN1 cause mucolipidosis type IV (Sun et al., 2000). Two mutations were discovered that account for 95% of disease chromosomes in the Ashkenazi Jew- ish population (Sun et al., 2000; Bassi et al., 2000; Bargal et al., 2000). Moreover, eight additional unique mutations have been identified in both Jewish and non-Jewish MLIV patients (Sun et al., 2000). MCOLN1 is a novel transient receptor potential (TRP) cation channel gene that is related to the Polycystin II sub- family of the TRP gene family. Mucolipin-1, the protein encoded by MCOLN1, is proposed to contain six trans- membrane domains, a putative calcium channel pore, a lipase serine active site, as well as a putative dileucine motif, which may serve as a late endosomal/lysosomal targeting motif (Sun et al., 2000). In this article we present a 1.4-Mb physical map surrounding the MCOLN1 gene, which maps to a re- gion of 19p13.3–p13.2 that has been linked to a variety of disorders for which the culprit genes have yet to be identified. A survey of recent publications reveals link- age or association of many human disorders to this region, including polycystic ovary syndrome (Urbanek et al., 2000), familial hypocalciuric hypercalemia type II (Heath and Leppert, 1992; Heath et al., 1993), famil- 1 To whom correspondence should be addressed at Harvard Insti- tute of Human Genetics, HIM Building, Room 422, 77 Avenue Louis Pasteur, Boston, MA 02115. Telephone: (617) 432-7025. Fax: (617) 432-3698. E-mail: slaugenh@helix.mgh.harvard.edu. Genomics 73, 203–210 (2001) doi:10.1006/geno.2001.6526, available online at http://www.idealibrary.com on 203 0888-7543/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.