This report describes childhood-onset neurodegeneration with brain atrophy (CONDBA); CONDBA exhibits autosomal dominant inheritance. The human gene implicated in this disease is UBTF, an HMG-box DNA-binding transcription factor that primarily regulates ribosomal RNA transcription. No gene orthologous to UBTF has been identified in Drosophila.
Multiple UAS constructs of the human Hsap\UBTF gene have been introduced into flies, including wild-type and a variant implicated in the human disease (using the UBTF1 isoform). Variant(s) implicated in human disease tested (as transgenic human gene, UBTF): the E210K variant form has been introduced into flies.
Experiments in flies confirm the pathogenicity of the E210K variant form. Pan-neuronal expression of the wild-type Hsap\UBTF does not reduce survival to adulthood, but pan-neuronal expression of the E210K variant form results in complete lethality prior to adulthood. Eye-specific expression of the wild-type results in eye defects and semi-lethality. Eye-specific expression of the E210K variant is much more dramatic: lethality at the pupal stage is observed; the heads are undeveloped and missing inside the pupal case.
[updated Jan. 2019 by FlyBase; FBrf0222196]
[NEURODEGENERATION, CHILDHOOD-ONSET, WITH BRAIN ATROPHY; CONDBA](https://omim.org/entry/617672)
[UPSTREAM BINDING TRANSCRIPTION FACTOR (RNA POLYMERASE I); UBTF](https://omim.org/entry/600673)
CONDBA is a severe progressive neurodegenerative disorder characterized by loss of motor and cognitive skills between ages 2 and 7 years. Affected individuals may have normal development or mild developmental delay, but all eventually lose all motor skills, resulting in inability to walk, absence of language, and profound intellectual disability (summary by Edvardson et al., 2017; pubmed:28777933). [from MIM:617672; 2019.01.15]
Childhood-onset neurodegeneration with brain atrophy (CONDBA) is caused by heterozygous mutation in the UBTF gene. [from MIM:617672; 2019.01.15]
Brain imaging shows progressive cerebral and cerebellar atrophy (summary by Edvardson et al., 2017; pubmed:28777933). [from MIM:617672; 2019.01.15]
Upstream binding factor (UBF or UBTF) is a transcription factor required for expression of the 18S, 5.8S, and 28S ribosomal RNAs, and components of the SL1 complex (TBP and multiple TBP-associated factors). [from MIM:600673; 2019.01.15]
UBTF encodes a member of the HMG-box DNA-binding protein family. The UBTF protein recognizes the ribosomal RNA gene promoter and activates transcription mediated by RNA polymerase I through cooperative interactions with the transcription factor SL1/TIF-IB complex; it binds specifically to the upstream control element. The UBTF protein may also play important roles in chromatin remodeling and pre-rRNA processing; its activity is regulated by both phosphorylation and acetylation. [Gene Cards, UBTF; 2019.01.15]
The 2 isoforms of UBTF appear to play different transcriptional regulatory roles: UBTF1 regulates ribosomal RNA transcription by RNA polymerase 1 (Pol I); UBTF2 regulates mRNA transcription by RNA polymerase 2 (Pol II) (FBrf0238028 and references cited therein).
No gene orthologous to UBTF has been identified in Drosophila; a number of genes exhibit similarity within an HMG-box domain.
