Sf. Kingsmore et al., POSITIONAL CLONING OF THE CHEDIAK-HIGASHI-SYNDROME GENE - GENETIC-MAPPING OF THE BEIGE LOCUS ON MOUSE CHROMOSOME-13, Journal of investigative medicine, 44(8), 1996, pp. 454-461
Citations number
41
Categorie Soggetti
Medicine, Research & Experimental","Medicine, General & Internal
Background: Chediak-Higashi syndrome (CHS) is a systemic disorder of h
uman and mouse (beige, bg) that is characterized by aberrant intracell
ular protein kinesis and lysosomal trafficking. Affected individuals e
xhibit a severe primary immune deficiency that principally affects the
function of granulocytes and cytolytic lymphocytes and partial oculoc
utaneous albinism, platelet dysfunction, and neurodegeneration. Chedia
k-Higashi syndrome is inherited as an autosomal recessive Mendelian tr
ait in human and mouse and maps on proximal mouse Chromosome 13. Metho
ds: To clone positionally the defective gene in CHS, we have generated
a large number of backcross mice who segregate for beige, Genomic DNA
from these mice was genotyped for 26 genetic markers known to map on
proximal mouse Chromosome 13. Results: By segregation analysis, bg was
localized to a 0.24 centiMorgan interval and was shown to cosegregate
with 6 genetic markers (Nid, Estm9, D13Mit56, D13Mit162, D13Mit237, a
nd D13Mit240). Two of these loci, Nid and Estm9, are genes and represe
nt candidates for bg, Nidogen (Nid) encodes an extracellular matrix pr
otein that is a component of basement membranes. Estm9 is a sequence t
hat is transcribed ubiquitously in mouse embryos and encodes a protein
of unknown function. Mutation analysis of Nid and Estm9 was undertake
n in 6 bg alleles; no differences were observed between bg and coisoge
nic controls by analysis of Northern blots, Southern blots, or by quan
titative reverse transcription and polymerase chain reaction. Conclusi
ons: These studies indicate that a genomic rearrangement affecting Nid
or Estm9 does not underlie bg, The bg locus has been localized on mou
se Chromosome 13 with sufficient precision to enable rapid cloning of
the bg nonrecombinant interval and eventual identification of the gene
for Chediak-Higashi syndrome among sequences within the interval.