Isolation of cDNAs from the human X chromosome and derivation of related STSs. Final progress report, April 1992--March 1995 Page: 3 of 6
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selection, direct screening of cDNA libraries, and other methods failed to provide bona fide
cDNAs. We uncovered two pseudogenes from these efforts. In recent months, we have identified
through GRAIL searches of genomic sequence developed over 150 kb distal to the fragile site an
exon which provided access to a cDNA from the region. This is a large mRNA, and a quite large
gene, but a key feature is that its 5' end is encoded by an exon carrying the FRAXE GCC repeat.
This is almost certainly the gene affected by FRAXE expansion and methylation, and we anticipate
submission of a manuscript regarding this gene by the end of the year. Dr. Yanghong Gu was
supported by the present grant for some of this work.
This gene was originally identified as an EST by Shoji Tsuji in Niigata using a method we
developed to clone human cDNAs specifically from somatic cell hybrids. The gene is located
immediately proximal to the IDS gene, as revealed by cosmid-based sequencing carried out in
collaboration with Dr. Gibbs. Indeed, TH4 represents an alternatively poly adenylated version of
the IDS transcript, thus it is not a novel gene.
This gene, iduronate sulfatase, results in Hunter syndrome when defective. In collaboration with
Dr. Gibbs, we have determined the sequence of 130 kb of DNA surrounding the IDS gene. This
has resulted in the identification of two novel genes (termed X and X') and a potential third (Y).
This work was recently published (Timms et al., Genome Res. 5:71, 1995) and points to the
utility of genomic sequence for gene identification and characterization. The sequence resolved the
highly similar and closely mapping X and X' genes, and also cleared up confusing issues
regarding the TH4 sequence (see above) and a very close by IDS pseudogene.
This fragile site was identified by Dr. Julia Parrish in the group through identification of cosmids
from the flow-sorted X chromosome library carrying high-GC content sequences. The probe used
for this (a cDNA termed H10) was obtained from Ben Oostra in Rotterdam as related to the fragile
X gene, FMR1. On further study, the H10 sequence unlikely to be expressed. A paper describing
the FRAXF mutation was published (Parrish et al., Nature Genet 8:229, 1994). This, like all
other folate sensitive fragile sites, is caused by expanded numbers of CGG repeats which are
methylated in their expanded versions. We were able to determine that FRAXF does not confer a
phenotype on individuals carrying the expanded version. However, access to the cDNAs
developed by Dr. Lee and coworkers determined that a member of a large gene family was present
adjacent to the FRAXF site. This family is known as the MAGE genes, and they were first
identified as tumor specific antigens present on the cell surfaces of melanoma and other
neuroectodermally derived tumors. Subsequent analysis by us and others has placed at least 12
MAGE genes in the interval of the X chromosome between FRAXF and GABRA3.
Ku autoantigen (Xq28)
Reciprocal probing efforts by Dr. Lee positioned this gene in Xq28, and we have sublocalized it to
a region just distal to FRAXF. As this gene has been assigned to an autosome by FISH analysis,
we were curious to determine whether the sequences on X corresponded to the authentic gene
encoding this protein, antibodies to which are often found in patients with lupus. Genomic
sequence analysis of cosmid subclones revealed that this is a pseudogene.
Na+..-dependent creatine transporter and 3A1/CDM (Xq28).
In the course of searching for additional CGG trinucleotide repeats present on the X chromosome,
we identified a cosmid located in Xq28,-which contains three genes identified through the use of
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Nelson, D.L. Isolation of cDNAs from the human X chromosome and derivation of related STSs. Final progress report, April 1992--March 1995, report, September 1, 1995; United States. (https://digital.library.unt.edu/ark:/67531/metadc624117/m1/3/: accessed April 19, 2019), University of North Texas Libraries, Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.