Objectives: 1) To confirm linkage of hereditary sensory neuropathy type 1 (
HSN-I) to human chromosome 9q22 in a large American family of German origin
. 2) To construct a yeast artificial chromosome (YAC) contig spanning the H
SN-I candidate interval. 3) To investigate the HSN-I contig for potential c
andidate genes. Background: HSN-I is a rare peripheral neuropathy character
ized by loss of temperature sensation, ulceration and osteomyelitis of the
digits, and subtle distal weakness. A gene for HSN-I has previously been ma
pped to human chromosome 9q22.1-q22.3 between markers D9S318 and D9S176 in
an 8-cM interval in four Australian families. Methods: In a large German-Am
erican family with HSN-I, genome-wide linkage analysis was performed on 68
family members extending over five generations and including 17 affected me
mbers. Genotyping was performed with PCR, and the resulting genotypes were
analyzed with two-point linkage analysis with Fastlink. A YAC contig was co
nstructed based on the Whitehead Institute YAC contig WC9.3. Results: Two-p
oint linkage analysis resulted in a maximum lod score of 8.2 at theta = 0 f
or marker D9S1815. Haplotype analysis locates the HSN-I gene between marker
s D9S1797 and D9S197. Using YAC clones from the Centre d'Etude du Polymorph
ism Humain YAC Library, we constructed a YAC contig spanning these markers.
Based on the radiation hybrid map of the human genome, we estimate that th
e size of this interval is less than 2,500 kb. Conclusions: Our study confi
rms linkage of a putative HSN-I gene to chromosome 9q22, considerably narro
ws the HSN-I locus, and provides a basis for identification of the HSN-I ge
ne.