and in the human hereditary motor and sensory 
neuropathy Charcot-Marie-Tooth disease, type lA 
(CMTIA). Point mutations could indeed be demon- 
strated in two strains of Trembler mice. 
In human CMTIA patients, the PMP-22 gene is 
located on a submicroscopically duplicated seg- 
ment of 1 7p without any evidence for its disruption. 
Thus the gene may be involved in both the human 
and the mouse mutations, but the pathophysiologi- 
cal mechanisms must be different. While amino acid 
substitutions in an important part of the protein are 
likely to be responsible in mice for the functional 
disruption, in humans the presence of an extra copy 
of an apparently undisrupted gene appears to result 
in a similar peripheral neuropathy phenotype. 
The gene for the small nuclear ribonucleoprotein 
polypeptide N (SNRPN) that is predominantly 
expressed in brain and plays a role in alternative 
splicing of calcitonin was mapped to two different 
chromosomes, in both humans and mice. The in- 
tron-containing, presumably functional genes were 
mapped to known homologous regions on human 
chromosome 15 and mouse chromosome 7, while 
the genes on the other two chromosomes represent 
processed pseudogenes. 
The Prader-Willi syndrome (PWS), characterized 
by congenital hypotonia, hypogonadism, mental re- 
tardation, and obesity due to lack of appetite con- 
trol, is often associated with a small deletion of re- 
gion 15qll.2-ql3. By studying patients with this 
syndrome, the SNRPN gene was mapped to the dele- 
tion interval critical for PWS. This is the first gene of 
known function to be mapped into the smallest de- 
letion overlap region. 
It is well established that genes contributing to 
this phenotype are maternally imprinted. In PWS 
deletion patients, the deleted chromosome is pater- 
nally derived. In PWS patients without the deletion, 
two maternally derived chromosomes are present 
(uniparental disomy). 
Since the SNRPN gene is predominantly expressed 
in the brain, and human fresh brain from these pa- 
tients is not easily available, studies were conducted 
in the mouse. They indicate that the SNRPN gene is 
indeed imprinted on the maternally derived chro- 
mosome. These findings support the hypothesis that 
this gene contributes to the deletion phenotype. 
Since no rearrangements or deletions of the gene 
were found in cases of atypical PWS, it is suggested 
that PWS is truly a microdeletion syndrome in which 
multiple genes are involved. The SNRPN gene is 
currently used as an anchor to isolate YACs from this 
region in which additional expressed genes will be 
identified and studied for uniparental expression. 
Mechanisms of Chromosome Translocations 
Two studies completed in the past year addressed 
the question of the origin of chromosome transloca- 
tions at the molecular level. A paternally derived 
t(X;4) translocation with a breakpoint disrupting 
the dystrophin gene was identified in a female with 
Duchenne muscular dystrophy. The translocation 
chromosomes were isolated in somatic cell hybrids, 
and the region involved in the translocation was 
cloned from both translocation chromosomes and 
normal homologues. 
When the sequences were compared, it became 
apparent that the translocation was associated with 
deletion of ~ 5 kb from the X chromosome. Further- 
more, a conserved sequence motif was detected ex- 
actly at the three breakpoints. This observation sug- 
gests a possible mechanism for this complex 
rearrangement that involves juxtaposition of the 
common sequence motif at the three sites and se- 
quence-specific breakage and recombination be- 
tween nonhomologous chromosomes. The results 
also illustrate that translocations that appear bal- 
anced at the microscopic level may be associated 
with the deletion of a significant amount of DNA 
when studied at the molecular level. 
In transgenic mice, microinjection of a cDNA con- 
struct containing the rat cDNAfor peripheral myelin 
protein P^ and integration of 50 copies of construct 
into the mouse genome resulted in reduced litter 
sizes. A reciprocal translocation between chromo- 
somes 1 and 1 4 was identified and characterized in 
embryos. Clusters of transgenes were localized by 
fluorescence in situ hybridization on both translo- 
cation chromosomes in the vicinity of the break- 
points. The endogenous P^ gene was mapped to 
chromosome 1 near the translocation breakpoint 
but was shown not to be disrupted by the transloca- 
tion event. These observations suggest models by 
which the insertion of the transgene array may have 
directly contributed to the translocation event. 
Mutations Causing Growth Hormone 
Insensitivity Syndrome (GHIS) 
This rare autosomal recessive disorder is charac- 
terized by severe growth retardation of postnatal on- 
set, normal or elevated serum growth hormone lev- 
els, decreased serum levels of insulin-like growth 
factor I, lack of clinical response to exogenous 
growth hormone, and absence of high-affinity serum 
growth hormone-binding activity. Dr. Francke's lab- 
oratory has continued to look for mutations in the 
growth hormone receptor (GHR) gene in this dis- 
order. All but 1 of 56 affected individuals from 
southern Ecuador were found to be homozygous for 
GENETICS 189 
