RESUMO
OBJECTIVES: The amino acid position 70 in HIV-1 reverse transcriptase (RT) plays an important role in nucleoside RT inhibitor (NRTI) resistance. K70R is part of the thymidine analog mutations, but also other amino acid changes have been associated with NRTI resistance, such as K70E and K70G. In this study, we investigated the in vivo selection of the HIV-1 RT mutations K70S and K70T and their in vitro effect on drug resistance and replication capacity. METHODS: Recombinant viruses with RT mutations were generated to measure the in vitro drug susceptibility and replication capacity. Bayesian network analysis and three-dimensional modeling were performed to understand the selection and impact of the RT70 mutations. RESULTS: K70S and K70T were found at a low frequency in RTI-experienced HIV-1 patients (0.10% and 0·20%). Baeyesian network learning identified no direct association with the in vivo exposure to any specific RTI. However, direct associations of K70S with mutations within the Q151M-complex and of K70T with K65R were observed. In vitro phenotypic testing revealed only minor effects of K70R/S/T as single mutations, associated with Q151M and within the context of the Q151M-complex. DISCUSSION: These results suggest that the selection of K70S/T and their phenotypic impact are influenced by the presence of other mutations in RT. However, the low impact on in vitro phenotype here observed, alongside with the low in vivo prevalence, the exclusive direct association with known major RTI mutations and the unknown correlation with in vivo response, do not yet necessitate the inclusion of K70S/T in drug resistance interpretation systems.
Assuntos
Aminoácidos , Farmacorresistência Viral , Transcriptase Reversa do HIV , HIV-1 , Mutação , Aminoácidos/química , Aminoácidos/efeitos dos fármacos , Aminoácidos/genética , Teorema de Bayes , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Células HEK293 , Infecções por HIV/virologia , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/efeitos dos fármacos , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Modelos Moleculares , Mutação/efeitos dos fármacos , Mutação/genéticaRESUMO
Here we report on 2 mentally retarded sisters with clinical signs and symptoms not seen in a previously delineated MCA/MR syndrome, i.e., normal pre- and perinatal history, severe mental retardation with severe delay in psychomotor development and without development of primary motor abilities and speech, characteristic face with maxillary hypoplasia, large mouth with down-turned corners, short philtrum and everted lower lip, associated with a remarkable ectomorphic habitus.
Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Deficiência Intelectual/genética , Somatotipos/genética , Adulto , Feminino , Luxação Congênita de Quadril/genética , Humanos , Fenótipo , Transtornos Psicomotores/genética , Escoliose/genéticaRESUMO
Two profoundly mentally retarded, unrelated males are reported with an unidentified multiple congenital anomaly/mental retardation syndrome, including early balding, patella luxations, small hands and feet, and hypogonadism, similar to a previous publication in this journal of a severely mentally retarded male patient with dysmorphic features.
Assuntos
Ossos Faciais/anormalidades , Deficiência Intelectual/genética , Crânio/anormalidades , Adulto , Alopecia/genética , Humanos , Masculino , Músculos/patologia , Patela/anormalidades , SíndromeRESUMO
In this report we describe two adult male patients with a chromosomal rearrangement involving the short arm of chromosome 18 and an acrocentric chromosome. In addition to moderate mental retardation and verbal disability they presented dysmorphic stigmata similar to those found in the Noonan syndrome.
Assuntos
Cromossomos Humanos Par 18 , Deficiência Intelectual/genética , Translocação Genética , Adulto , Cromossomos Humanos Par 13 , Humanos , Cariotipagem , Masculino , FenótipoRESUMO
Four different balanced X/autosome translocations: 46,X,t(X;9)(p11;q13); 46,X,t(X;12) (p11;q12); 46,X,t(X;15)(q12;p11) and 46,X,t(X;19)(q26;p12) are described in four female patients. The effect of X/autosome translocations on physical and sexual development of these women and their offspring is discussed.
Assuntos
Cromossomos Humanos 13-15 , Cromossomos Humanos 19-20 , Cromossomos Humanos 6-12 e X , Fertilidade , Translocação Genética , Cromossomo X , Adulto , Estatura , Criança , Bandeamento Cromossômico , Mecanismo Genético de Compensação de Dose , Feminino , Humanos , Cariotipagem , Linfócitos/ultraestrutura , FenótipoRESUMO
Two adult, mentally retarded males with the typical features of the Coffin-Lowry syndrome are reported. Further family investigation led to the same diagnosis in a 2.5-year-old male cousin, and to the identification of five female carriers, with variable clinical expression of this X-linked inherited mental retardation syndrome.
Assuntos
Doenças do Desenvolvimento Ósseo/genética , Deficiência Intelectual/genética , Adulto , Criança , Pré-Escolar , Expressão Facial , Feminino , Dedos/anormalidades , Ligação Genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Cromossomo XRESUMO
Triploid-diploid mosaicism in fibroblasts of a deeply mentally retarded 21-year-old female is reported. The relevant findings in 2n/3n mosaicism are reviewed and discussed.
Assuntos
Diploide , Deficiência Intelectual/genética , Adulto , Aberrações Cromossômicas/genética , Transtornos Cromossômicos , Feminino , Humanos , MosaicismoRESUMO
Partial 18q12 trisomy, due to intrachromosomal duplication, was found in a severely mentally retarded boy. The finding of nonspecific dysmorphism in this patient demonstrates that trisomy of band 18q12 is accompanied by neither a full nor an incomplete 18 trisomy phenotype, indicating that this phenotype may be due solely to trisomy of the 18q11 band.
Assuntos
Cromossomos Humanos 16-18 , Cromossomos Humanos 6-12 e X , Deficiência Intelectual/genética , Trissomia , Anormalidades Múltiplas/genética , Criança , Humanos , Cariotipagem , Masculino , FenótipoRESUMO
In this report a description is given of the Aarskog syndrome in six males belonging to three different families. Partial expression of the syndrome was confirmed in two of the three examined obligate female heterozygotes, who had short stature, small hands and feet, short neck, and a round face with widow's peak and, in one of them, ptosis of the eyelids.
Assuntos
Anormalidades Múltiplas/genética , Disostose Craniofacial/genética , Face/anormalidades , Genitália Masculina/anormalidades , Hipertelorismo/genética , Deformidades Congênitas dos Membros , Feminino , Transtornos do Crescimento/genética , Humanos , Masculino , Linhagem , Fatores Sexuais , SíndromeRESUMO
Two brothers with Coffin syndrome are presented and the fifteen other cases availabe in the literature are reviewed. The molecular defect causing this clinically recognizable syndrome is unknown, and the mode of inheritance may be a sex-linked recessive, but a sex-limited autosomal dominant or autosomal dominant with variable degree of expression cannot be fully excluded at the present time.