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Molecular Characterization of TUB, TULP1, and TULP2, Members of the Novel Tubby Gene Family and Their Possible Relation to Ocular Diseases

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Molecular Characterization of TUB, TULP1, and TULP2, Members of the Novel Tubby Gene Family and Their Possible Relation to Ocular Diseases Proc. Natl. Acad. Sci. USA Vol. 94, pp. 3128–3133, April 1997 Genetics Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases MICHAEL A. NORTH*, JUERGEN K. NAGGERT†,YINGZHUO YAN*, KONRAD NOBEN-TRAUTH†, AND PATSY M. NISHINA†‡ *Sequana Therapeutics, Inc., La Jolla, CA 92037; and †The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609 Communicated by Elizabeth S. Russell, The Jackson Laboratory, Bar Harbor, ME, January 16, 1997 (received for review September 7, 1996) ABSTRACT Tubby, an autosomal recessive mutation, sion no. U52433) and ET-3636.p01.d01 (nucleotides 1323– mapping to mouse chromosome 7, was recently found to be the 1421, 99 bp) by random hexamer priming, as described (6). result of a splicing defect in a novel gene with unknown These probes were used to screen '1.2 3 106 plaque forming function. Database searches revealed that sequences corre- units of a human adult brain cDNA library in lgt11, plated sponding to the C terminus of the tub protein were highly according to the manufacturer’s instructions (CLONTECH). conserved across a number of species including humans, mice, Duplicate membrane filters were hybridized with labeled Caenorhabditis elegans, Arabidopsis, rice, and maize, and that probe in 10% dextran sulfate, 1% SDS, 1 M NaCl, 100 mgyml tub was a member of a gene family. We describe here, TUB, the of salmon testes DNA at 658C for 18 hr. After hybridization, human homolog of mouse tub, and two newly characterized filters were washed at 658Cin23SSC (13 SSC 5 0.15 M family members, TULP1 for tubby like protein 1 and TULP2. sodium chloridey0.015 M sodium citrate, pH 7)/0.1% SDS for These three family members, which differ in the N-terminal 45 min and twice in 0.23 SSC/0.1% SDS for 45 min each and half of the protein, share 60–90% amino acid identity across positive plaques identified by autoradiography. Following their conserved C-terminal region and have distinct tissue plaque purification, cDNA inserts were PCR amplified using expression patterns. Alternatively spliced transcripts with 5* lgt11 primers (BRL) and directly cloned into pCR2.1 for variable sequences, three of which have been identified for the sequencing, according to the manufacturer’s instructions (In- tubby gene, may mediate tissue specific expression. We also vitrogen). Automated fluorescence sequencing was used to report that TUB, TULP1, and TULP2 map to human chromo- characterize the cDNA clones (Prism, Applied Biosystems). somes 11p15.4, 6p21.3, and 19q13.1, respectively. TULP1 and Cloning of TULP1 cDNA. Approximately 1 3 106 plaque- TULP2 map within the minimal intervals identified for reti- forming units of human retinal cDNA lgt11 library (CLON- nitis pigmentosa 14 on chromosome 6p21.3 and cone-rod TECH) were hybridized with a 32P-labeled EcoRIySacII frag- dystrophy on chromosome 19q13.1. TULP1 and TULP2, which ment (1–962 bp) of I.M.A.G.E. EST clone 221670 (Research are expressed in the retina, make excellent candidates for Genetics, Huntsville, AL) at 658C overnight. The membranes these ocular diseases as a mutation within the tub gene is were washed sequentially for 1 hr each with 23 SSC/0.1% SDS known to lead to early progressive retinal degeneration. at 508C, 13 SSC/0.1% SDS at 508C, and 0.53 SSC/0.1% SDS at 608C. Thirty positive plaques were purified and phage Mice homozygous for a splicing defect in the C terminus of positives of insert size .1 kb were digested with EcoRI and the tub gene are characterized by progressive retinal and subcloned into pUC9. One of these clones was a full-length cochlear degeneration (1, 2), maturity-onset obesity with cDNA containing the entire ORF. Independently, to isolate insulin resistance, and impaired glucose tolerance (3). We the flanking 59 sequences, nested oligonucleotide primer pairs recently identified tub as a novel gene with high expression AP1 and hMan2-R3 59-AGCTCCTCGGAGCCCTAGC-39 in the retina, brain, and testis (4). Analysis of the tub gene (nucleotides 2017–2035 of the TULP1 sequence), as well as revealed sequence similarity to the p46 mouse cDNA (5) and AP2 and hMan2-R1 59-ACATGCCTCGATCCATGCC-39 an integrated molecular analysis of genomes and their (nucleotides 979–997), were used in subsequent rounds of expression (I.M.A.G.E.) expressed sequence tag (EST) amplification of Marathon–Ready brain cDNA (CLON- clone from a human retinal cDNA library, suggesting that tub TECH), according to manufacturer’s protocol. Amplification is a member of a family of genes. To further characterize this products were gel purified (Qiagen, Chatsworth, CA) and family and explore the possibility that its members may be sequenced automatically (Prism, Applied Biosystems) or man- candidate genes for diseases that exhibit similar phenotypes ually by dideoxy cycle sequencing (Sequitherm, Epicentre as tubby, we obtained and characterized human full-length Technologies, Madison, WI). Alternately, gel purified prod- cDNAs for TUB, for the gene corresponding to the human ucts were subcloned into the TA-cloning vector according to EST, now referred to as TULP1 for tubby like protein 1, as the manufacturer’s instruction (Invitrogen) and plasmids were well as for a new member, TULP2. isolated by a standard protocol (6) prior to sequencing. Cloning of TULP2 cDNA. A PCR product amplified from MATERIALS AND METHODS a mouse testis cDNA library using primers MP46.1 59- Cloning of TUB cDNA. 32P-labeled hybridization probes TCTACAGAGACAAACTATGCCC-39 and MP46.2 59- GGAAATGTGCTACACCATC CTC-3 was used as a were prepared from two tub exon trap products, ET- 9 probe to screen 1 3 106 plaque-forming units of human testis 3636.p01.a04 (nucleotides 1422–1593, 171 bp, GenBank acces- cDNA library in lDR2 (CLONTECH). Hybridization, washes, and radiography were carried out as described for The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. §1734 solely to indicate this fact. Abbreviation: EST, expressed sequence tag. Data deposition: The sequences reported in this paper have been Copyright q 1997 by THE NATIONAL ACADEMY OF SCIENCES OF THE USA deposited in the GenBank database (accession nos. U82467–U8469). 0027-8424y97y943128-6$2.00y0 ‡To whom reprint requests should be addressed. e-mail: pmn@aretha. PNAS is available online at http:yywww.pnas.org. jax.org. 3128 Downloaded by guest on September 30, 2021 Genetics: North et al. Proc. Natl. Acad. Sci. USA 94 (1997) 3129 FIG.1. (a) Comparison of nucleotide sequence and deduced amino acid sequence of the 59 splice variants of TUB and HSU54644. Break in sequence denotes the intronyexon junction. (b) Comparison of mouse tub and human TUB, TULP1, and TULP2. p, Conserved identical amino acids; ~, conservative replacements. The alignments were produced with the computer program CLUSTAL W1.6 (13). cloning of the TUB cDNAs. Thirty-four positive clones were amplified and sequenced from DNA of 10 unrelated indi- detected after overnight exposure and after tertiary screen- viduals using primers TULP2-F1 59-ATCGTGGATC- ing, 28 positives were isolated and converted to plasmid CCAAACACC-39 and TULP2-R1 59-GCTGGCAAGGG- DNA in pDR2. The C-terminal intron of TULP2 was PCR TATGGTATT-39. Downloaded by guest on September 30, 2021 3130 Genetics: North et al. Proc. Natl. Acad. Sci. USA 94 (1997) Southern Blot Analysis. Southern blots of EcoRI-digested CAGGACACCTTTGCCTTCT-39, hMan1-R2 59-GC- genomic DNA from a number of animal species were obtained GATCTCCCTTCCTTCCT-39), the 39 noncoding region for from CLONTECH. They were hybridized with a 32P-labeled TUB (hMan6.4-F1 59-TGCCTGGGAATCCTGCTGC-39 and HindIII fragment (281–1833 bp) of TUB cDNA and a 32P- hMan6.4-R1 59-TCCTAAGGGTCCTGCCACT-39), and for labeled EcoRIyBstXI TULP1 fragment (the first 365 bp of 59 TULP1 (hMan2-F7 59-CGAAAACGGAGCAAGACAG-39, end of clone 221670). Blots were washed in 23 SSC/0.05% SDS hMan2-R7 59-TATGAGGCTCTCCAGCGTC-39), using the at room temperature two times for 10 min and at 608C for 20 MACVECTOR computer program (Oxford). Primers for TULP2 min, then twice in 0.23 SSC/0.1% SDS at 608C for 20 min each. were constructed from an exon in the 39 portion of the gene Northern Blot Analysis. Human multiple tissue Northern (HP46.F1 59-CCACTAAATGAACAGGAGTCGC-39 and blots (MTN I, II, and III; CLONTECH) were hybridized with HP46.R2 59-TTGGAAGTTCTTCACCGAAGCC-39). After the probes described above for Southern blot analyses, in 103 confirming by sequencing that the appropriate product was Denhardt’s/2% SDS, 100 mgyml of sheared salmon sperm amplified, the retention patterns for each oligonucleotide pair DNA, and 50% formamide at 428C for 18 hr, then washed in were obtained by PCR assay in the Stanford G3 Radiation Hybrid 23 SSC/0.05% SDS at room temperature three times for 10 panel (9) as previously described (10). hMan1-F2yR2 amplifies a min and in 0.13 SSC/0.1% SDS at 508C two times for 20 min. band of '480 bp, constant hamster specific bands were observed The same blots were hybridized with the 32P-labeled product at '150, 200, and 213 bp. hMan6.4-F1yR1 amplifies a 221-bp of TULP2 (amplified using primers HP46.F1 59-CCACTA- product with constant hamster DNA-specific bands at '290 and AATGAACAGGAGTCGC-39 and HP46.R1 59-GAAACTG- 320 bp. The product of hMan2-F7yR2 is 92 bp in length with a GACAAGCAGATGCTG-39). The hybridization was done in constant hamster DNA amplified band at '230 bp. HP46.F1yR2 ExpressHyb solution (CLONTECH) at 608C for 2 hr, accord- amplifies a 162-bp fragment.
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