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T B Friedman

Publications and source records attributed to T B Friedman.

At least 19 recordsLinked to original sources
PubMed2001

Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F.

Human chromosome 10q21-22 harbors USH1F in a region of conserved synteny to mouse chromosome 10. This region of mouse chromosome 10 contains Pcdh15, encoding a protocadherin gene that is mutated in ames waltzer and causes deafness and vestibular dysfunction. Here we report two mutations of protocadherin 15 (PCDH15) found in two families segregating Usher syndrome type 1F. A Northern blot probed with the PCDH15 cytoplasmic domain showed expression in the retina, consistent with its pathogenetic role in the retinitis pigmentosa associated with USH1F.

Aged↗
PubMed2000

Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23.

Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, approximately 0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.

Alleles↗
PubMed2000

OTOF encodes multiple long and short isoforms: genetic evidence that the long ones underlie recessive deafness DFNB9.

We have recently reported that OTOF underlies an autosomal recessive form of prelingual sensorineural deafness, DFNB9. The isolated 5-kb cDNA predicted a 1,230 amino acid (aa) C-terminus membrane-anchored cytosolic protein with three C2 domains. This protein belongs to a family of mammalian proteins sharing homology with the Caenorhabditis elegans fer-1. The two other known members of this family, dysferlin and myoferlin, both have six predicted C2 domains. By northern blot analysis, a 7-kb otoferlin mRNA could be detected in the human brain. We isolated the corresponding cDNA, which is expected to encode a 1,977-aa-long form of otoferlin with six C2 domains. A 7-kb cDNA derived from the murine orthologous gene, Otof, was also identified in the inner ear and the brain. The determination of the exon-intron structure of the human and murine genes showed that they are composed of 48 coding exons and extend approximately 90 kb and approximately 80 kb, respectively. Alternatively spliced transcripts could be detected that predict several long isoforms (six C2 domains) in humans and mice and short isoforms (three C2 domains) only in humans. Primers were designed to explore the first 19 OTOF exons, henceforth permitting exploration of the complete coding sequence of the gene in DFNB9 patients. In a southwestern Indian family affected by DFNB9, a mutation in the acceptor splice site of intron 8 was detected, which demonstrates that the long otoferlin isoforms are required for inner ear function.

Alternative Splicing↗
PubMed1992

The urate oxidase gene of Drosophila pseudoobscura and Drosophila melanogaster: evolutionary changes of sequence and regulation.

The urate oxidase (UO) transcription unit of Drosophila pseudoobscura was cloned, sequenced, and compared to the UO transcription unit from Drosophila melanogaster. In both species the UO coding region is divided into two exons of approximately equal size. The deduced D. pseudoobscura and D. melanogaster UO peptides have 346 and 352 amino acid residues, respectively. The nucleotide sequences of the D. pseudoobscura and D. melanogaster UO protein-coding regions are 82.2% identical whereas the deduced amino acid sequences are 87.6% identical with 42 amino acid changes, 33 of which occur in the first exon. Although the UO gene is expressed exclusively within the cells of the Malpighian tubules in both of these species, the temporal patterns of UO gene activity during development are markedly different. UO enzyme activity, UO protein, and UO mRNA are found in the third instar larva and adult of D. melanogaster but only in the adult stage of D. pseudoobscura. The intronic sequences and the extragenic 5' and 3' flanking regions of the D. pseudoobscura and D. melanogaster UO genes are highly divergent with the exception of eight small islands of conserved sequence along 772 bp 5' of the UO protein-coding region. These islands of conserved sequence are possible UO cis-acting regulatory elements as they reside along the 5' flanking DNA of the D. melanogaster UO gene that is capable of conferring a wild-type D. melanogaster pattern of UO regulation on a UO-lacZ fusion gene.

Amino Acid Sequence↗
PubMed1992

A frameshift mutation in the HuP2 paired domain of the probable human homolog of murine Pax-3 is responsible for Waardenburg syndrome type 1 in an Indonesian family.

Waardenburg syndrome type 1 (WS1) is an autosomal dominant disorder characterized by deafness, dystopia canthorum, heterochromia iridis, white forelock, and premature greying. A similar phenotype is caused in the mouse by mutations in the Pax-3 gene. This observation, together with comparisons of conserved syntenies in the murine and human genetic maps, suggested that at least some WS1 mutations should occur in HuP2, the probable human homolog of Pax-3. Two mutations in the HuP2 sequence of individuals with WS1 have been reported recently. Both of them occur in the highly conserved paired box region of the gene, which encodes a DNA binding domain. The functional consequences of these mutations are at present speculative. We report here a 14 bp deletion in the paired domain encoded by exon 2 of HuP2 in an Indonesian family segregating for WS1. This frameshift mutation results in a premature termination codon in exon 3. The HuP2 product is a truncated protein lacking most of the paired domain and all of the predicted homeo domain. We propose that the WS1 phenotype in this family is due to loss of function of HuP2 and discuss two mechanisms for the dominant effect of this mutation.

Amino Acid Sequence↗
PubMed1992

Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium.

Previous studies have localized the gene for Waardenburg syndrome (WS) type I to the distal portion of chromosome 2q, near the ALPP locus. We pooled linkage data obtained from 41 WS type I and 3 WS type II families which were typed for six polymorphic loci on chromosome 2q in order to refine the location of the WS locus (WS1) and evaluate the extent of genetic heterogeneity. In the course of this work, we developed diagnostic criteria for genetic and phenotypic studies. Our findings, based on two-locus and multilocus analysis using a linkage map established from reference pedigrees, suggest that there are two or more mutations causing WS, one of which (i.e., WS1) is located on chromosome 2q, between the ALPP and FN1 loci, at distances of 7.8 cM and 11.2 cM for each marker, respectively. The results also indicate that WS1 is responsible for the illness in approximately 45% of all families in this sample. However, the odds favoring this position over a location between ALPP and SAG are only 2:1 when alternate assumptions about the proportion of linked families are considered. We conclude that a more saturated map of this region of chromosome 2q, including highly polymorphic markers, will be needed to accurately distinguish linked families and, ultimately, isolate the mutant gene.

Alkaline Phosphatase↗
PubMed1991

Species differences in the temporal pattern of Drosophila urate oxidase gene expression are attributed to trans-acting regulatory changes.

The Drosophila melanogaster urate oxidase (UO)-encoding gene is expressed in the third-instar larva and adult. In contrast, the Drosophila pseudoobscura UO gene is only expressed in the adult, whereas the Drosophila virilis UO gene is expressed only in the third-instar larva. UO activity in these three Drosophila species is detected exclusively within the Malpighian tubules. By using P-element mediated germ-line transformation, UO genes from D. pseudoobscura and D. virilis were integrated into the D. melanogaster genome. The D. virilis and D. pseudoobscura UO transgenes were expressed in the third-instar larva and adult Malpighian tubules, which is the D. melanogaster temporal pattern of UO gene expression. These observations indicate that differences in the temporal patterns of regulation of UO genes among these three Drosophila species are not likely to be due to evolutionary changes in the sequence or complement of UO cis-acting regulatory elements. The species differences in UO regulation are probably the result of changes in one or more trans-acting factors required for UO gene expression in the third-instar larval and adult stages.

Age Factors↗
PubMed1991

The faint band/interband region 28C2 to 28C4-5(-) of the Drosophila melanogaster salivary gland polytene chromosomes is rich in transcripts.

Urate oxidase mRNA and five other transcripts map along 38 kb of DNA in the region 28C on the Drosophila melanogaster second chromosome. Three biotinylated restriction fragments from this 38 kb of DNA, one from each end and one from the middle, were individually hybridized in situ to slightly stretched salivary gland polytene chromosomes. The data from these in situ hybridizations in combination with the transcription map of the 38 kb of DNA indicate that: (i) there are six discrete RNA species encoded along the 38 kb of DNA and (ii) these six transcripts map to the faint band/interband region which includes the proximal edge of 28C1, the three faint bands, 28C2, 28C3 and 28C4-5(-), and the adjacent interband chromatin. Our data are consistent with the few published studies directly demonstrating that faint band/interband regions of the Drosophila melanogaster salivary gland polytene chromosomes code for a high density of transcripts.

Animals↗
PubMed1991

Waardenburg syndrome (WS): the analysis of a single family with a WS1 mutation showing linkage to RFLP markers on human chromosome 2q.

Waardenburg syndrome type I (WS1; MIM 19350) is caused by a pleiotropic, autosomal dominant mutation with variable penetrance and expressivity. Of individuals with this mutation, 20%-25% are hearing impaired. A multilocus linkage analysis of RFLP data from a single WS1 family with 11 affected individuals indicates that the WS1 mutation in this family is linked to the following four marker loci located on the long arm of chromosome 2: ALPP (alkaline phosphatase, placental), FN1 (fibronectin 1), D2S3 (a unique-copy DNA segment), and COL6A3 (collagen VI, alpha 3). For the RFLP marker loci, a multilocus linkage analysis using MLINK produced a peak lod (Z) of 3.23 for the following linkage relationships and recombination fractions (theta i): (ALPP----.000----FN1)----.122----D2S3----.267----CO L6A3. A similar analysis produced a Z of 6.67 for the following linkage relationships and theta i values among the markers and WS1: (FN1----.000----WS1----.000----ALPP)----.123----D2S 3----.246----COL6A3. The data confirm the conclusion of Foy et al. that at least some WS1 mutations map to chromosome 2q.

Chromosomes, Human, Pair 2↗
PubMed1990

Molecular characterization of the Drosophila melanogaster urate oxidase gene, an ecdysone-repressible gene expressed only in the malpighian tubules.

The urate oxidase (UO) gene of Drosophila melanogaster is expressed during the third-instar larval and adult stages, exclusively within a subset of cells of the Malpighian tubules. The UO gene contains a 69-base-pair intron and encodes mature mRNAs of 1,224, 1,227, and 1,244 nucleotides, depending on the site of 3' endonucleolytic cleavage prior to polyadenylation. A direct repeat, 5'-AAGTGAGAGTGAT-3', is the proposed cis-regulatory element involved in 20-hydroxyecdysone repression of the UO gene. The deduced amino acid sequences of UO of D. melanogaster, rat, mouse, and pig and uricase II of soybean show 32 to 38% identity, with 22% of amino acid residues identical in all species. With use of P-element-mediated germ line transformation, 826 base pairs 5' and approximately 1,200 base pairs 3' of the D. melanogaster UO transcribed region contain all of the cis elements allowing for appropriate temporal regulation and Malpighian tubule-specific expression of the UO gene.

Amino Acid Sequence↗
PubMed1990

Mouse and hamster mutants as models for Waardenburg syndromes in humans.

Four different Waardenburg syndromes have been defined based upon observed phenotypes. These syndromes are responsible for approximately 2% of subjects with profound congenital hearing loss. At present, Waardenburg syndromes have not been mapped to particular human chromosomes. One or more of the mouse mutant alleles, Ph (patch), s (piebald), Sp (splotch), and Mior (microphthalmia-Oak Ridge) and the hamster mutation Wh (anophthalmic white) may be homologous to mutations causing Waardenburg syndromes. In heterozygotes, phenotypic effects of these four mouse mutations and the hamster mutation are similar to the phenotypes produced by different Waardenburg syndrome mutations. The chromosomal locations and syntenic relationships associated with three of the four mouse mutant genes have been used to predict human chromosomal locations for Waardenburg syndromes: (1) on chromosome 2q near FN1 (fibronectin 1), (2) on chromosome 3p near the proto-oncogene RAF1 or 3q near RHO (rhodopsin), and (3) on chromosome 4p near the proto-oncogene KIT. Waardenburg syndromes show extensive intrafamilial phenotypic variability. Results of our studies with the hamster mutation Wh suggest that this variability may be explained in part by modifier genes segregating within families.

Adult↗
PubMed1987

Cloning of a Drosophila melanogaster adenine phosphoribosyltransferase structural gene and deduced amino acid sequence of the enzyme.

The Aprt locus of Drosophila melanogaster encodes the structural gene for adenine phosphoribosyltransferase (APRT). DNA cloned from microdissected salivary gland polytene chromosome region 62B7-12 was used in conjunction with chromosome walking and hybrid selection of mRNA to isolate the Aprt gene. Aprt lies at cytogenetic position 62B9 and is closely flanked by other genes of unknown function. Nucleotide sequencing shows that four APRT cDNAs have a common 5' terminus with an apparent cap consensus sequence but two different 3' sites of polyadenylation. The distribution of conserved amino acid sequences in APRT from vertebrates, insects and bacteria suggests that they may have shared a common ancestral gene for this ubiquitous enzyme.

Adenine Phosphoribosyltransferase↗
PubMed1986

Cloning a cDNA for Drosophila melanogaster urate oxidase.

A cDNA library from third-instar larval Malpighian tubules of Drosophila melanogaster was constructed and screened for urate oxidase (UO) clones by hybridization selection. The coding sequence for UO was mapped by in situ hybridization to position 28C on the left arm of chromosome 2. The UO activity in Drosophila shows a complex developmental profile. A UO cDNA was used as a probe of Northern blots of poly(A) + RNA from various stages of development. The data show that there is a direct correlation between the transcriptional activity of the UO locus as evidenced by the quantitative changes of UO mRNA and the levels of UO activity and protein during development.

Animals↗
PubMed1985

On the loss of uricolytic activity during primate evolution--I. Silencing of urate oxidase in a hominoid ancestor.

Urate oxidase activity is not detectable in liver homogenates from the gibbon, orangutan, chimpanzee, gorilla and human. Liver homogenates from five genera of Old World and two genera of New World monkeys have easily detectable levels of urate oxidase activity. There is no evidence for extant detectable intermediate steps in the loss of urate oxidase activity in the hominoids. Urate oxidase activity from Old World and New World monkeys is stable, a simple observation which debunks a long-standing myth. Urate oxidase activity was silenced in an ancestor to the five living genera of hominoids after divergence from the Old World monkeys.

Animals↗
PubMed1978

Galactose metabolism in Dictyostelium discoideum. Regulation of galactose-1-phosphate-uridyl transferase during growth and development.

Dictyostelium discoideum is able to metabolize [1-14C]galactose to 14CO2 despite the observation that galactose is inhibitory with respect to growth. Galactose-1-phosphate uridyl transferase activity is present throughout growth and development and varies in activity only slightly during the entire life cycle of D. discoideum, in contrast to the rapid increase in UDP-glucose 4-epimerase activity during development. Therefore, in D. discoideum, these two enzymes of the Leloir pathway are independently regulated, unlike E. coli where these enzymes are coordinately controlled.

Dictyostelium↗