RESUMO
Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.
Assuntos
Alelos , Transtornos do Crescimento/genética , Doenças do Cabelo/genética , Homozigoto , Ictiose/genética , Progéria/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Animais , Dano ao DNA , Genes Letais , Genes Recessivos , Transtornos do Crescimento/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Progéria/metabolismo , Fator de Transcrição TFIIH/genética , Fator de Transcrição TFIIH/metabolismo , Transcrição Gênica , Raios UltravioletaRESUMO
We compared the value of 7.5 Nm external rotation stress in diagnosing tibiofibular syndesmotic injuries of the ankle on lateral radiographs with radiostereometric analysis (RSA) in 10 cadaveric legs. After sectioning 2 ligaments, RSA showed an increase in posterior translation and external rotation of the fibula. This increase in posterior translation was smaller than the posterior displacement of the fibula on the lateral radiograph, and RSA showed mainly an increase in external rotation of the fibula that can not be measured on conventional radiographs. We conclude that instability of the syndesmosis in cadaveric ankles can be detected with 7.5 Nm external rotation stress RSA, but that external rotation stress lateral radiography is unreliable.
