The oculocerebrorenal syndrome of Low (OCRL) is an X-linked inborn error of metabolism of unknown etiology. Affected males are retarded and have congenital cataracts and renal tubular dysfunction. The locus for OCRL has been mapped to the Xq25 region by linkage to restriction fragment length polymorphisms (RFLPs) in Xq24-26 and by the occurrence of OCRL in a female with an X/3 translocation with breakpoint at Xq25. A yeast artificial chromosome (YAC) containing a 100-120 kb human insert was isolated in another, collaborating laboratory and made available to this laboratory. This YAC, RS88, appears to contain sequences from either side of the breakpoint in the X;3 translocation in the female with OCRL. Using sequences from within RS88, overlapping genomic sequences in lambda or cosmid vectors will be isolated until the entire region around the breakpoint have been cloned. All DNA from this region will be tested for whether it contains exons of a candidate gene based on (i) conservation of nucleic acid homology between man and other mammals, (ii) expression of the sequence in lens, kidney, m brain and fibroblasts, (all target tissues for OCRL), (iii) demonstration of mutation, deletional or otherwise, of these putative exonic sequences in OCRL probands. When a candidate gene is identified, (1) its entire mRNA sequence and genomic structure will be characterized. (2) the mutations responsible for the disease will be determining by sequencing the exons and intron-exon boundaries of the gene in the DNA of patients (3) antibodies to the gene product will be raised and used to determine the tissue(s) in which the gene is expressed and the cellular and subcellular localization of the gene product. (4) the promoter and enhancer sequences responsible for control of gene expression will be identified. The long-term objective is to identify the gene for a human mental retardation syndrome through its location rather than its function and then to characterize the gene and in expression as well as the mutations responsible for the disease in man. The ultimate goal is to understand what the gene product is and how defects in the gene produce disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD023245-04
Application #
3323307
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1987-09-01
Project End
1993-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
4
Fiscal Year
1990
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
Janne, P A; Suchy, S F; Bernard, D et al. (1998) Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice. J Clin Invest 101:2042-53
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
Olivos-Glander, I M; Janne, P A; Nussbaum, R L (1995) The oculocerebrorenal syndrome gene product is a 105-kD protein localized to the Golgi complex. Am J Hum Genet 57:817-23
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
Reilly, D S; Nussbaum, R L (1990) Parental origin of de novo translocation in a patient with both an inherited and a de novo chromosome translocation. Am J Med Genet 37:429-30

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