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Biomedical subjects

T B Friedman

Publications and source records attributed to T B Friedman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA).

Waardenburg syndrome (WS) is a clinically and genetically heterogeneous disease accounting for >2% of the congenitally deaf population. It is characterized by deafness in association with pigmentary anomalies and various defects of neural crest-derived tissues. At least four types are recognized (WS1, WS2, WS3 and WS4) on the basis of clinical and genetic criteria. Two previously described families seemed to delineate a new subtype characterized by WS2 in conjunction with ocular albinism (OA). Since mutations in the MITF gene are responsible for some instances of WS2, we screened for mutations in one of the WS2-OA families and discovered a 1 bp deletion in exon 8 of MITF. OA previously has been associated with compound heterozygosity for a mutant TYR allele and the TYR(R402Q) allele, a functionally significant polymorphism that is associated with moderately reduced tyrosinase catalytic activity. In this family, all of the individuals with the OA phenotype are either homozygous or heterozygous for TYR(R402Q), and heterozyous for the 1 bp deletion in MITF This suggests that the WS2-OA phenotype may result from digenic interaction between a gene for a transcription factor (MITF) and a gene that it regulates (TYR).

Albinism, Ocular↗
PubMed1997

The incidence of deafness is non-randomly distributed among families segregating for Waardenburg syndrome type 1 (WS1).

Waardenburg syndrome (WS) is caused by autosomal dominant mutations, and is characterised by pigmentary anomalies and various defects of neural crest derived tissues. It accounts for over 2% of congenital deafness. WS shows high variability in expressivity within families and differences in penetrance of clinical traits between families. While mutations in the gene PAX3 seem to be responsible for most, if not all, WS type 1, it is still not clear what accounts for the reduced penetrance of deafness. Stochastic events during development may be the factors that determine whether a person with a PAX3 mutation will be congenitally deaf or not. Alternatively, genetic background or non-random environmental factors or both may be significant. We compared the likelihoods for deafness in affected subjects from 24 families with reported PAX3 mutations, and in seven of the families originally described by Waardenburg. We found evidence that stochastic variation alone does not explain the differences in penetrances of deafness among WS families. Our analyses suggest that genetic background in combination with certain PAX3 alleles may be important factors in the aetiology of deafness in WS.

Alleles↗
PubMed1996

Effects of Pax3 modifier genes on craniofacial morphology, pigmentation, and viability: a murine model of Waardenburg syndrome variation.

Waardenburg syndrome type 1 is caused by mutations in PAX3. Over 50 human PAX3 mutations that lead to hearing, craniofacial, limb, and pigmentation anomalies have been identified. A PAX3 mutant allele, segregating in a family, can show reduced penetrance and variable expressivity that cannot be explained by the nature of the mutation alone. The Mus musculus Pax3 mutation Spd (Splotch-delayed, Pax3Spd), coisogenic on the C57BL/6J (B6) genetic background, produces in heterozygotes a white belly spot with 100% penetrance and very few other anomalies. By contrast, many Spd/+ BC1 progeny [F1 female Spd/+ (female Spd/+ B6 x male +/+ Mus spretus) x male +/+ B6] exhibit highly variable craniofacial and pigmentary anomalies. Of the BC1 Spd/+ progeny, 23.9% are estimated to be nonviable, and 32.1% are nonpenetrant for the white belly spot. The penetrance and expressivity of the Spd/+ genotype are controlled in part by the genetic background and the sex of the individual. A minimum of two genes interact with Spd to influence the craniofacial features of these mice. One of these genes may be either X-linked or sex-influenced, while the other is autosomal. The A-locus (Agouti) or a gene closely linked to A also plays a role in determining craniofacial features. At least one additional gene, possibly the A-locus or a gene linked to A, interacts with Spd and determines the presence and size of the white belly spot. The viability of BC1 mice is influenced by at least three factors: Spd, A-locus alleles or a gene closely linked to the A-locus, and the sex of the mouse. These BC1 mice provide an opportunity to identify genes that interact with and modify the expression of Pax3 and serve as a model to identify the genes that modify the expression of human PAX3 mutations.

Alleles↗
PubMed1996

Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome.

Craniofacial-deafness-hand syndrome (MIM 122880) is inherited as an autosomal dominant mutation characterized by the absence or hypoplasia of the nasal bones, profound sensorineural deafness, a small and short nose with slitlike nares, hypertelorism, short palpebral fissures, and limited movement at the wrist and ulnar deviations of the fingers. In a family of three affected individuals with this syndrome, a mother and two children, a missense mutation (Asn47Lys) in the paired domain of PAX3 was initially detected by SSCP analysis. PCR amplification using an oligonucleotide with a terminal 3'-residue match for the C-to-G transversion in codon 47 showed the presence of this mutation in the DNA from all affected members. The DNA from unaffected members were refractory to PCR amplification with the mutation-specific oligonucleotide but did amplify a control primer pair in the same PCR reaction tube. A previously described missense mutation in this same codon (Asn47His) is associated with Waardenburg syndrome type 3 (Hoth et al., 1993). Substitution of a basic amino acid for asparagine at residue 47, conserved in all known murine Pax and human PAX genes, appears to have a more drastic effect on the phenotype than missense, frameshift and deletion mutations of PAX3 that cause Waardenburg syndrome type 1.

Amino Acid Sequence↗
PubMed1995

A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17.

Two percent of the residents of Bengkala, Bali, have profound, congenital, neurosensory, nonsyndromal deafness due to an autosomal recessive mutation at the DFNB3 locus. We have employed a direct genome-wide disequilibrium search strategy, allele-frequency-dependent homozygosity mapping (AHM), and an analysis of historical recombinants to map DFNB3 and position the locus relative to flanking markers. DFNB3 maps to chromosome 17, closest to D17S261, pRM7-GT and D17S805. In individuals homozygous for DFNB3, historical recombinant genotypes for the flanking markers, D17S122 and D17S783, place DFNB3 in a 5.3 cM interval of the pericentromeric region of chromosome 17 on a refined linkage map of 17p-17q12. Based on conserved synteny, the murine sh2 gene may be the homologue of DFNB3.

Alleles↗
PubMed1995

Analysis of short tandem repeat (STR) allele frequency distributions in a Balinese population.

Genotypes for 53 short tandem repeat (STR) markers distributed at an average of 39 cM intervals throughout the genome were determined for 46 individuals from the village of Bengkala, Bali. This village of approximately 2200 individuals has an oral and written tradition suggesting genetic bottlenecks. The allele frequency distributions in Bengkala were compared with distributions obtained by typing individuals in the CEPH data base using a Kolmogorov-Smirnov two sample test. Twenty-eight of the 53 markers showed differences (P < 0.05) in distribution between the two populations. Allele frequencies of tetranucleotide STRs were much more similar between the two populations than were those of dinucleotide STRs (P < 0.043). Population heterogeneity in Bengkala was indicated by an excess of observed homozygosity, deviations from Hardy-Weinberg equilibrium at seven loci, and significant allelic associations between physically unlinked loci. In addition to providing information pertinent to the issue of genetic diversity of STRs in the human population, these analyses serve as a resource to map a gene causing non-syndromal autosomal recessive deafness in Bengkala, and to corroborate the anthropological study of the history and social structure of the village.

Alleles↗
PubMed1995

Congenital non-syndromal autosomal recessive deafness in Bengkala, an isolated Balinese village.

Bengkala is an Indonesian village located on the north shore of Bali that has existed for over 700 years. Currently, 2.2% of the 2185 people in this village have profound congenital deafness. In response to the high incidence of deafness, the people of Bengkala have developed a village specific sign language which is used by many of the hearing and deaf people. Deafness in Bengkala is congenital, sensorineural, non-syndromal, and caused by a fully penetrant autosomal recessive mutation at the DFNB3 locus. The frequency of the DFNB3 mutation is estimated to be 9.4% among hearing people who have a 17.2% chance of being heterozygous for DFNB3.

Alleles↗
PubMed1994

Locus heterogeneity for Waardenburg syndrome is predictive of clinical subtypes.

Waardenburg syndrome (WS) is a dominantly inherited and clinically variable syndrome of deafness, pigmentary changes, and distinctive facial features. Clinically, WS type I (WS1) is differentiated from WS type II (WS2) by the high frequency of dystopia canthorum in the family. In some families, WS is caused by mutations in the PAX3 gene on chromosome 2q. We have typed microsatellite markers within and flanking PAX3 in 41 WS1 kindreds and 26 WS2 kindreds in order to estimate the proportion of families with probable mutations in PAX3 and to study the relationship between phenotypic and genotypic heterogeneity. Evaluation of heterogeneity in location scores obtained by multilocus analysis indicated that WS is linked to PAX3 in 60% of all WS families and in 100% of WS1 families. None of the WS2 families were linked. In those families in which equivocal lod scores (between -2 and +1) were found, PAX3 mutations have been identified in 5 of the 15 WS1 families but in none of the 4 WS2 families. Although preliminary studies do not suggest any association between the phenotype and the molecular pathology in 20 families with known PAX3 mutations and in four patients with chromosomal abnormalities in the vicinity of PAX3, the presence of dystopia in multiple family members is a reliable indicator for identifying families likely to have a defect in PAX3.

Chromosome Mapping↗
PubMed1993

An intraspecific gene duplication polymorphism of the urate oxidase gene of Drosophila virilis: a genetic and molecular analysis.

Nineteen strains of Drosophila virilis from diverse geographic locations were examined by genetic and molecular analyses, revealing (a) 12 strains with a single copy of the urate oxidase (UO) gene per haploid genome and (b) 7 strains with a tandem duplication of the UO locus. The D. virilis strains with the UO duplication appear to have identical restriction maps of this region, implying either a single origin for the duplication or several similar events occurring at a hot spot. On the basis of the location of the duplication breakpoints and the restriction sites flanking these breakpoints, this duplication probably arose through nonhomologous recombination involving either a breakage and rejoining event or replication slippage. because documented cases of intraspecific gene duplication polymorphism are rare, the D. virilis UO duplication will be useful in identifying the molecular event giving rise to a gene duplication.

Animals↗
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↗