CONSTRUCTION OF A GENE MAP OF THE NEPHRONOPHTHISIS TYPE-1 (NPHP1) REGION ON HUMAN-CHROMOSOME 2Q12-Q13

A gene for the autosomal recessive kidney disorder juvenile nephronoph thisis (NPH) is located on chromosome 2q between markers D2S1893 and D 2S1888. Recently, the presence of large homozygous deletions was descr ibed in the majority of NPH patients. We constructed an integrated YAC /PAC contig of 54 markers and 30 PAC clones that encompasses this dele tion and the flanking inverted duplication. Thirty-six novel sequence- tagged site markers were generated for this region of 2-3 Mb, 22 of wh ich represent PAC ends. Ten of 18 multiplex NPH families show a homozy gous deletion for 8 consecutive markers. BlastN database search and ex pressed sequence tag (EST) mapping led to the localization of 18 EST c lones to the integrated contig, representing 11 putative transcribed s equences. Seven EST clones were localized to the NPHP1 region between D2S1893 and D2S1888. Two EST clones, zc07all from a human parathyroid tumor library and yy63e10 hem a multiple sclerosis lesion library, are located in the deletion region. PCR amplification experiments indicat e that zc07all represents a chimeric cDNA. Through FISH analysis the N PHP1 deletion region was localized to 2q12-q13. In summary, our study provides a high-resolution physical map of the NPHP1 region with 7 pre cisely localized expressed sequences, 2 of which have recently been sh own to be part of a gene for NPH. These data will alleviate the identi fication of further genes of a homozygous gene deletion syndrome in pa tients with NPH and oculomotor apraxia and will be instrumental in the characterization of the molecular mechanism leading to the large homo zygous deletion in this region. The data furthermore provide an import ant step toward the construction of a sequence-ready PAC contig of thi s region. (C) 1998 Academic Press.