Positional cloning of the chediak-higashi syndrome gene in human and mouse

S. F. Kingsmore, V. T. Tchernev, Q. A. Nguyen, R. F. Holcombe, J. A. Ashley, M. Lovett, M. D.F.S. Barbosa

Research output: Contribution to journalArticlepeer-review


Chediak-Higashi syndrome is a primary immune deficiency disease of human (CHS) and mouse (beige, bg). Affected individuals have defective granulocyte and natural killer cell activity, pathognomonic giant vesicles in many cell types, and typically die in childhood of infection or malignancy. Since attempts to identify the genetic defect in CHS directly have been thwarted by absence of chromosomal assignment of CHS or pedigrees adequate for linkage analysis, we have undertaken positional cloning of bg as an antecedent to identification of the CHS gene. Positional cloning is an approach to identifying a disease gene based solely on its chromosomal location, without regard to etiology. Our experiments have: 1. Localized bg to a 0.24±0.17 centiMorgan interval on proximal mouse chromosome 13; 2. Cloned the bg nonrecombinant interval in contiguous yeast artificial chromosomes (YACs); 3. Isolated expressed sequences from a 650-kb critical region YAC using direct selection; 4. Characterized 50 direct selection products by sequence analysis, RT-PCR, Northern analysis, and YAC assignment. We plan to identify the defective gene in the bg mouse by examining genes corresponding to direct selection products for mutations in bg alleles. Identification of the bg gene will facilitate understanding of mechanisms of regulation of protein trafficking to lysosomes, and of the contribution of vesicular sorting to diverse cellular functions. Cloning of the human homolog of the bg mutation will enable examination for causality in CHS.

Original languageEnglish
Pages (from-to)64A
JournalJournal of Investigative Medicine
Issue number1
StatePublished - 1996
Externally publishedYes


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