RESUMO
The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
Assuntos
Encefalopatias/genética , Epilepsia/genética , Rim Fundido/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Osteocondrodisplasias/genética , Adolescente , Sequência de Aminoácidos , Animais , Encefalopatias/etiologia , Criança , Pré-Escolar , Epilepsia/complicações , Evolução Molecular , Feminino , Frequência do Gene , Humanos , Lactente , Masculino , Camundongos , Modelos Moleculares , Proteínas Nucleares/química , Proteínas Nucleares/deficiência , Fenótipo , Estabilidade Proteica , Síndrome , Fatores de Elongação da Transcrição/química , Fatores de Elongação da Transcrição/genética , Adulto Jovem , Peixe-Zebra/genéticaRESUMO
Accumulating evidence suggests that individuals with sarcomeric hypertrophic cardiomyopathy (HCM) carrying MYH7 mutations may have a worse prognosis than MYBPC3 mutation carriers. Myocardial deformation analysis is superior to standard echocardiography in detecting subtle myocardial dysfunction and scar formation, but studies evaluating the association with HCM genotype are scarce. We therefore aimed to compare myocardial strain parameters between MYBPC3 and MYH7 mutation carriers with proven HCM. Participants of the prospective Graz HCM Registry carrying at least one causative mutation in MYBPC3 (n = 39) or MYH7 (n = 18) were enrolled. MYBPC3 mutation carriers were older, predominantly male and more often treated with an implantable cardioverter-defibrillator (39% vs. 0%; p = 0.002). Using analyses of covariance, there were no significant differences between MYBPC3 and MYH7 mutation carriers with regard to left ventricular global longitudinal strain (estimated marginal means ± standard deviation: -16.9 ± 0.6% vs. -17.3 ± 0.9%; p = 0.807) and right ventricular 6-segments endocardial strain (-24.3 ± 1.0% vs. 26.3 ± 1.5%; p = 0.285). Our study suggests, that myocardial deformation analysis may not be helpful in concluding on the underlying HCM genotype, and vice versa.