The oculocerebrorenal syndrome of Lowe (LOCRS) is an X-linked inborn error of metabolism of unknown etiology. Affected males are retarded and have congenital cataracts and renal tubular dysfunction. Carrier females frequently show lens opacities that may aid in heterozygote detection but are not fully sensitive or specific. Prenatal diagnosis is not possible. The locus for LOCRS has been mapped to the Xq25 region by linkage to restriction fragment length polymorphisms (RFLPs) in Xq24-26 and by the occurrence of LOCRS in a female with an X/3 translocation with breakpoint at Xq25. The project will be carried out in two phases: Phase 1: We propose to use the X;3 translocation cell line to generate somatic cell hybrids in which the der X and der 3 are isolated away from the normal X. These hybrids will allow us to map a set of independent cosmid clones from the Xq24-26 region with respect to the Xq25 breakpoint. Cosmids that flank the breakpoint will be used to search for a number of RFLPs in order to generate highly informative flanking markers for LOCRS. These RFLPS will be tested for linkage to LOCRS in a set of 6 families segregating for the disease. If recombination is seen with a particular flanking cosmid, additional cosmids will be analyzed for RFLPs until a pair of tightly linked flanking markers is identified. Phase 2: The molecular distance between the LOCRS locus and the Xq24-26 cosmid sequences will be estimated in two different ways. First, large restriction fragments from the X;3 translocation line and the hybrids containing derX or der3 will be separated by pulsed-field gel electrophoresis and probed with Xq24-26 cosmid sequences to look for an aberrant fragment cuased by the breakpoint. A cosmid within 500 kb of the breakpoint is likely to be found among the set of greater than 50 cosmid clones that will be available. Second, a panel of DNA from 41 independent patients with LOCRS will be screened with these same Xq24-26 cosmids to look for an interstitial deletion affecting the LOCRS. Identification of a cosmid sequence within a measurable molecular distance of the LOCRS locus is an important first step towards gene isolation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD023245-03
Application #
3323310
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1987-09-01
Project End
1990-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Nussbaum, R L; Orrison, B M; Janne, P A et al. (1997) Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet 99:145-50
Lin, T; Orrison, B M; Leahey, A M et al. (1997) Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome. Am J Hum Genet 60:1384-8
Janne, P A; Rochelle, J M; Martin-DeLeon, P A et al. (1995) Mapping of the 75-kDa inositol polyphosphate-5-phosphatase (Inpp5b) to distal mouse chromosome 4 and its exclusion as a candidate gene for dysgenetic lens. Genomics 28:280-5
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Janne, P A; Dutra, A S; Dracopoli, N C et al. (1994) Localization of the 75-kDa inositol polyphosphate-5-phosphatase (INPP5B) to human chromosome band 1p34. Cytogenet Cell Genet 66:164-6
Leahey, A M; Charnas, L R; Nussbaum, R L (1993) Nonsense mutations in the OCRL-1 gene in patients with the oculocerebrorenal syndrome of Lowe. Hum Mol Genet 2:461-3
Lee, J T; Murgia, A; Sosnoski, D M et al. (1992) Construction and characterization of a yeast artificial chromosome library for Xpter-Xq27.3: a systematic determination of cocloning rate and X-chromosome representation. Genomics 12:526-33
Okabe, I; Bailey, L C; Attree, O et al. (1992) Cloning of human and bovine homologs of SNF2/SWI2: a global activator of transcription in yeast S. cerevisiae. Nucleic Acids Res 20:4649-55
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