A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele,

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A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele, Rainer.

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A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele, Rainer Ruf, Adelheid M. Mueller, Karl S. Hiller, Matthias T.F. Wolf, Maria J. Schuermann, Achim Becker, Ralf Birkenhäger, Ralf Sudbrak, Hans C. Hennies, Peter Nürnberg, Friedhelm Hildebrandt The American Journal of Human Genetics Volume 71, Issue 5, Pages 1161-1167 (November 2002) DOI: 10.1086/344395 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Haplotype results on chromosome 1p36 performed for refinement of the NPHP4 locus in affected offspring from three consanguineous families with NPHP. Family, generation, and individual numbers are indicated above haplotypes. Paternal haplotypes are shown on blue background, and maternal haplotypes are shown on yellow background. A recombination in the maternal haplotype, which was directly observed in parent-to-child transmission in this pedigree, is shown on orange background. At left, 8 published microsatellites are given in italic, and 38 newly generated microsatellites are given in roman. Flanking markers to the published 2.1-Mb critical NPHP4 interval are depicted in red. Informative alleles are underlined. Haplotypes homozygous in continuity are encased in boxes. Homozygosity mapping revealed a p-terminal recombinant for marker D1E23 (asterisks) on the basis of heterozygosity in individuals F30 II-2 and F30 II-3 and an observed recombinant for marker SNP-KIAA0720-Ex19 (asterisks) in individual F30 II-3, thus refining the critical genetic region to a secure interval <1.2 Mb. On the basis of a significant LOD score yielded for F30 alone (Schuermann et al. 2002), this refinement yields secure borders. Further refinement was achieved through heterozygosity for markers D1E19 and D1S2870 (double asterisks) in individuals F32 II-1 and F60 II-1, respectively. This refines the critical genetic region to a suggestive interval <700 kb. Because of the presence of only two affected individuals in each family, this refinement is only suggestive. p-ter = Telomeric; cen = centromeric; nd = not done. The American Journal of Human Genetics 2002 71, 1161-1167DOI: (10.1086/344395) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 Positional cloning strategy for the NPHP4 gene, on human chromosome 1p36. A, Genetic map position for microsatellites used in linkage mapping of NPHP4 (see fig. 1). Sex-averaged genetic distance (in cM) from the Marshfield map was used. Published flanking markers are underlined (Schuermann et al. 2002). p-ter = Telomeric; cen = centromeric. B, Physical map distances of critical microsatellites relative to D1S2660. The secure 1.2-Mb critical interval (solid bar) and the 700-kb suggestive critical interval (stippled bar) are delimited by the newly identified secure flanking markers (asterisks) and suggestive flanking markers (double asterisks) defined by haplotype analysis (see fig. 1). Below the axis, known genes (green), predicted unknown genes (blue), and the NPHP4 gene (also known as “Q9UFQ2”) are represented as arrows in the direction of transcription. C, Genomic organization of NPHP4, with exons indicated by vertical hatches and numbered. D, Exon structure of NPHP4 cDNA. Blackened and unblackened boxes represent the 30 exons encoding nephroretinin. The number of the first codon of each exon is indicated; exons beginning with the second or third base of a codon are indicated by “b” or “c,” respectively. At bottom, locations of the 11 different mutations identified in eight kindreds with NPHP4 mutations are shown. fs = Frameshift. E, NPHP4 mutations occurring homozygously in affected individuals from five consanguineous families (underlined). Compound heterozygous mutations are not shown. Mutated nucleotides and altered amino acids are depicted on gray background. The American Journal of Human Genetics 2002 71, 1161-1167DOI: (10.1086/344395) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 Northern blot analysis of the NPHP4 expression pattern. A multiple-tissue northern blot with human adult poly(A)+ RNA was hybridized with a 584-bp NPHP4 human DNA probe. Expression of a 5.0-kb transcript (arrowhead) is apparent in all tissues studied, with highest expression being in skeletal muscle. The American Journal of Human Genetics 2002 71, 1161-1167DOI: (10.1086/344395) Copyright © 2002 The American Society of Human Genetics Terms and Conditions