ABSTRACT
GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.
Subject(s)
Gene Expression Regulation, Developmental/genetics , Induced Pluripotent Stem Cells/metabolism , Neurodevelopmental Disorders/metabolism , Neurons/metabolism , Ribonucleoproteins, Small Nuclear/metabolism , SMN Complex Proteins/genetics , Alleles , Amino Acid Sequence , Animals , Child, Preschool , Developmental Disabilities/genetics , Drosophila/genetics , Drosophila/growth & development , Female , Gene Knockdown Techniques , Gene Ontology , HEK293 Cells , Humans , Loss of Function Mutation , Male , Muscle Hypotonia/genetics , Myoclonic Cerebellar Dyssynergia/genetics , Neurodevelopmental Disorders/diagnostic imaging , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/physiopathology , Pedigree , Polymorphism, Single Nucleotide , RNA-Seq , Ribonucleoproteins, Small Nuclear/genetics , Rigor Mortis/genetics , SMN Complex Proteins/metabolismABSTRACT
CONTEXT: Aromatase is a key enzyme in local estrogen production by androgen conversion, especially in women post-menopause. There have been controversies concerning aromatase localization in breast carcinomas and its association with current histopathological variables. MATERIAL AND METHODS: Using polyclonal antibody immunohistochemistry we assessed (by intensity and percentage scores) the immunolocalization of aromatase in 70 tissue samples, and described particularities within the molecular subtypes of breast cancer. RESULTS: Aromatase was found in all tissue compartments: tumor (95.7%), stroma (58.6%) and adipose tissue (94.3%). Aromatase expression in tumor cells correlated inversely with tumor grading (p=-0.361, p=0.027), and positively with estrogen receptor status (ER, p=0.143, p<0.001). Dividing the study group by intrinsic subtypes, a strongly inversely association between tumor aromatase and grading (p=-0.486, p<0.001), and between stromal aromatase and Ki67-index (p=-0.448, p=0.048) was observed in luminal A breast cancer. Tumor aromatase and ER percentage scores had stronger correlations in luminal B HER2 negative (p=0.632, p=0.002), and positive (p=0.324, p=0.026) tumors. In contrast, in triple negative tumors, a positive association stromal aromatase and Ki67 index (p=-0.359, p=0.007) was observed. CONCLUSION: Local aromatase was linked to better tumor differentiation and proliferation in luminal breast subtypes, and not in triple negative cases, suggesting a potential prognostic role of aromatase in breast carcinomas.
