An in vivo mutation from leucine to tryptophan at position 210 in human immunodeficiency virus type 1 reverse transcriptase contributes to high-level resistance to 3'-azido-3'-deoxythymidine

Hooker, David J.; Tachedjian, Gilda; Solomon, Ajantha; Gurusinghe, Asitha; Land, Sally; Birch, Chris; Anderson, Jeffrey L.; Roy, Bidyut; Arnold, Edward; Deacon, Nicholas J.

doi:10.1128/jvi.70.11.8010-8018.1996

“…4). This apparent exclusion of the mutations at codons 70 and 210 is consistent with previously published data on the evolution of zidovudineresistant genotypes in treated patients (4,9). Taken together with the data obtained with the sequences stored in the Stanford database, this suggests that the concomitant detection of the L210W and K70R mutations in the same genome is only transient.…”

Section: Scope Of Studysupporting

confidence: 91%

“…The nucleoside analog 3Ј-azido-3Ј-deoxythymidine (zidovudine) is the most widely used clinical therapy for HIV-1 infection. However, zidovudine monotherapy invariably results in the appearance of HIV-1-resistant strains with multiple mutations in the RT gene, especially M41L, D67N, K70R, L210W, T215Y/F, and K219Q (2,4,9,15). Thus, the high prevalence of these mutations (Fig.…”

Section: Scope Of Studymentioning

confidence: 99%

Mutation Patterns of the Reverse Transcriptase and Protease Genes in Human Immunodeficiency Virus Type 1-Infected Patients Undergoing Combination Therapy: Survey of 787 Sequences

Yahi

¹

,

Tamalet

²

,

Tourres

³

et al. 1999

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The aim of the present study was to evaluate the resistance-associated mutations in 302 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving combination therapy and monitored in Marseille, France, hospitals from January 1997 to June 1998. In the reverse transcriptase (RT) gene, the most frequent mutations were found at codons 215 (53%), 41 (34%), and 67, 70, 184, and 210 (>20%). One deletion and two insertions in the β3-β4 hairpin loop of the finger subdomain (codon 69) were detected. Interesting associations and/or exclusions of specific mutations were observed. In 96% of RT genes, a mutation at codon 70 (most frequently, K70R) was associated with a wild-type genotype at position 210 (P < 10−5). Similarly, a mutation at codon 210 (most frequently, L210W) was generally associated with mutations at codons 41 (92%) and 215 (96%) but not at codon 219 (16%) or codon 70 (4%) (P < 10−5). In the protease gene, the most prevalent mutations were at codons 63 (84%), followed by codons 10, 36, 71, 77, and 93 (ca. 20%). As for RT, pairwise associations of mutations were observed. Analysis of the mutation patterns for patients with undetectable HIV-1 loads revealed a high proportion (65%) of wild-type RT genotypes but only 18% wild-type protease genotypes. For patients with high viral loads (>100,000 copies/ml), more than 50% of the RT and protease genes displayed three or more mutations. The significant correlation between the level of viremia in plasma and the number of resistance mutations in the protease (P = 0.007) and RT (P = 0.00078) genes strengthens the importance of defining the genotype of the predominant HIV-1 quasispecies before initiating antiretroviral therapy.

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“…The leucine 445 residue is located in the tenth transmembrane domain of pendrin. The leucine to tryptophan substitution is not conservative, and it can reasonably be expected that the replacement of an aliphatic by an aromatic amino acid residue alters the conformation of the protein [Sanchez et al, 1994;Hooker et al, 1996;Basani et al, 1997]. The phenotypic findings of the patients are presented in Table I.…”

Section: Resultsmentioning

confidence: 99%

Pendred syndrome: Phenotypic variability in two families carrying the same PDS missense mutation

Masmoudi¹,

Charfedine²,

Hmani³

et al. 2000

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Pendred syndrome comprises congenital sensorineural hearing loss, thyroid goiter, and positive perchlorate discharge test. Recently, this autosomal recessive disorder was shown to be caused by mutations in the PDS gene, which encodes an anion transporter called pendrin. Molecular analysis of the PDS gene was performed in two consanguineous large families from Southern Tunisia comprising a total of 23 individuals affected with profound congenital deafness; the same missense mutation, L445W, was identified in all affected individuals. A widened vestibular aqueduct was found in all patients who underwent computed tomography (CT) scan exploration of the inner ear. In contrast, goiter was present in only 11 affected individuals, who interestingly had a normal result of the perchlorate discharge test whenever performed. The present results question the sensitivity of the perchlorate test for the diagnosis of Pendred syndrome and support the use of a molecular analysis of the PDS gene in the assessment of individuals with severe to profound congenital hearing loss associated with inner ear morphological anomaly even in the absence of a thyroid goiter.

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“…The leucine 445 residue is located in the tenth transmembrane domain of pendrin. The leucine to tryptophan substitution is not conservative, and it can reasonably be expected that the replacement of an aliphatic by an aromatic amino acid residue alters the conformation of the protein [Sanchez et al, 1994; Hooker et al, 1996; Basani et al, 1997].…”

Section: Resultsmentioning

confidence: 99%

Pendred syndrome: Phenotypic variability in two families carrying the samePDS missense mutation

Masmoudi¹,

Charfedine

²

,

Hmani³

et al. 2000

View full text Add to dashboard Cite

Pendred syndrome comprises congenital sensorineural hearing loss, thyroid goiter, and positive perchlorate discharge test. Recently, this autosomal recessive disorder was shown to be caused by mutations in the PDS gene, which encodes an anion transporter called pendrin. Molecular analysis of the PDS gene was performed in two consanguineous large families from Southern Tunisia comprising a total of 23 individuals affected with profound congenital deafness; the same missense mutation, L445W, was identified in all affected individuals. A widened vestibular aqueduct was found in all patients who underwent computed tomography (CT) scan exploration of the inner ear. In contrast, goiter was present in only 11 affected individuals, who interestingly had a normal result of the perchlorate discharge test whenever performed. The present results question the sensitivity of the perchlorate test for the diagnosis of Pendred syndrome and support the use of a molecular analysis of the PDS gene in the assessment of individuals with severe to profound congenital hearing loss associated with inner ear morphological anomaly even in the absence of a thyroid goiter.

show abstract

An in vivo mutation from leucine to tryptophan at position 210 in human immunodeficiency virus type 1 reverse transcriptase contributes to high-level resistance to 3'-azido-3'-deoxythymidine

Cited by 98 publications

References 55 publications

Mutation Patterns of the Reverse Transcriptase and Protease Genes in Human Immunodeficiency Virus Type 1-Infected Patients Undergoing Combination Therapy: Survey of 787 Sequences

Mutation Patterns of the Reverse Transcriptase and Protease Genes in Human Immunodeficiency Virus Type 1-Infected Patients Undergoing Combination Therapy: Survey of 787 Sequences

Pendred syndrome: Phenotypic variability in two families carrying the same PDS missense mutation

Pendred syndrome: Phenotypic variability in two families carrying the samePDS missense mutation

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