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Vol. 12, Issue 5, 713-728, May 2002

Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17p11.2 and the Syntenic Region of the Mouse

Weimin Bi,^1,6 Jiong Yan,^1,6 Pawe Stankiewicz,¹ Sung-Sup Park,^1,7 Katherina Walz,¹ Cornelius F. Boerkoel,¹ Lorraine Potocki,^1,3 Lisa G. Shaffer,¹ Koen Devriendt,⁴ Magorzata J.M. Nowaczyk,⁵ Ken Inoue,¹ and James R. Lupski^1,2,3,8

Departments of ¹ Molecular & Human Genetics, ² Pediatrics, Baylor College of Medicine, ³ Texas Children's Hospital, Houston, Texas 77030, USA; ⁴ Centre for Human Genetics, University Hospital Gasthuisberg, Catholic University of Leuven, B-3000 Leuven, Belgium; ⁵ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4J9, Canada

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with behavioral abnormalities and sleep disturbance. Most patients have the same ~4 Mb interstitial genomic deletion within chromosome 17p11.2. To investigate the molecular bases of the SMS phenotype, we constructed BAC/PAC contigs covering the SMS common deletion interval and its syntenic region on mouse chromosome 11. Comparative genome analysis reveals the absence of all three ~200-kb SMS-REP low-copy repeats in the mouse and indicates that the evolution of SMS-REPs was accompanied by transposition of adjacent genes. Physical and genetic map comparisons in humans reveal reduced recombination in both sexes. Moreover, by examining the deleted regions in SMS patients with unusual-sized deletions, we refined the minimal Smith-Magenis critical region (SMCR) to an ~1.1-Mb genomic interval that is syntenic to an ~1.0-Mb region in the mouse. Genes within the SMCR and its mouse syntenic region were identified by homology searches and by gene prediction programs, and their gene structures and expression profiles were characterized. In addition to 12 genes previously mapped, we identified 8 new genes and 10 predicted genes in the SMCR. In the mouse syntenic region of the human SMCR, 16 genes and 6 predicted genes were identified. The SMCR is highly conserved between humans and mice, including 19 genes with the same gene order and orientation. Our findings will facilitate both the identification of gene(s) responsible for the SMS phenotype and the engineering of an SMS mouse model.

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⁶ These authors contributed equally to this work.

⁷ Present address: Department of Clinical Pathology, Seoul National University Hospital, Seoul 110-744, South Korea.

⁸ Corresponding author.

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12:713-728 ©2002 by Cold Spring Harbor Laboratory Press  ISSN 1088-9051/02 $5.00

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