ABSTRACT
We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.
ABSTRACT
The effects of calmidazolium (10(-7) mol/l) and db cAMP (10(-3) mol/l) on the longitudinal internal resistance (ri) in the rabbit sinus node strips were studied by means of microelectrode and extracellular recording techniques. Calmidazolium (CDZ) decreased ri by 27%. An addition of db cAMP to the CDZ-containing Tyrode potentiated this effect by further 14%. db cAMP initially decreased ri by 17%, then it enhanced this resistance by 7% above the pretreatment control value. An addition of CDZ to the db cAMP-containing Tyrode reduced ri by 41% below the pretreatment control. Possible mechanisms underlying these effects were discussed in terms of cAMP, Cai, and calmodulin action on the cell coupling.
