Novel missense mutation in the bZIP transcription factor, MAF, associated with congenital cataract, developmental delay, seizures and hearing loss (Aymé-Gripp syndrome).

BACKGROUND: Cataract is a major cause of severe visual impairment in childhood. The purpose of this study was to determine the genetic cause of syndromic congenital cataract in an Australian mother and son. METHOD: Fifty-one genes associated with congenital cataract were sequenced in the proband using a custom Ampliseq library on the Ion Torrent Personal Genome Machine (PGM). Reads were aligned against the human genome (hg19) and variants were annotated. Variants were prioritised for validation by Sanger sequencing if they were novel, rare or previously reported to be associated with paediatric cataract and were predicted to be protein changing. Variants were assessed for segregation with the phenotype in the affected mother. RESULT: A novel likely pathogenic variant was identified in the transactivation domain of the MAF gene (c.176C > G, p.(Pro59Arg)) in the proband and his affected mother., but was absent in 326 unrelated controls and absent from public variant databases. CONCLUSION: The MAF variant is the likely cause of the congenital cataract, Asperger syndrome, seizures, hearing loss and facial characteristics in the proband, providinga diagnosis of Aymé-Gripp syndrome for the family.

Biochemical and structural studies of conserved Maf proteins revealed nucleotide pyrophosphatases with a preference for modified nucleotides.

Maf (for multicopy associated filamentation) proteins represent a large family of conserved proteins implicated in cell division arrest but whose biochemical activity remains unknown. Here, we show that the prokaryotic and eukaryotic Maf proteins exhibit nucleotide pyrophosphatase activity against 5-methyl-UTP, pseudo-UTP, 5-methyl-CTP, and 7-methyl-GTP, which represent the most abundant modified bases in all organisms, as well as against canonical nucleotides dTTP, UTP, and CTP. Overexpression of the Maf protein YhdE in E. coli cells increased intracellular levels of dTMP and UMP, confirming that dTTP and UTP are the in vivo substrates of this protein. Crystal structures and site-directed mutagenesis of Maf proteins revealed the determinants of their activity and substrate specificity. Thus, pyrophosphatase activity of Maf proteins toward canonical and modified nucleotides might provide the molecular mechanism for a dual role of these proteins in cell division arrest and house cleaning.

Small Maf proteins in mammalian gene control: mere dimerization partners or dynamic transcriptional regulators?

The small Maf basic leucine zipper (bZIP) proteins MafF, MafG and MafK, while modest in size, have emerged as crucial regulators of mammalian gene expression. Intriguingly, small Mafs do not contain an obvious transcriptional activation domain. However, previously perceived as "mere" partner molecules conferring DNA binding specificity to complexes with larger bZIP proteins, such as the CNC family member Nrf2, it has become clear that small Maf proteins are essential and dynamically regulated transcription factors. Current data suggest stringent control of small Maf protein function through transcriptional and post-translational mechanisms. Initial gene targeting experiments revealed considerable functional redundancy among small Maf proteins in vivo. This was not unexpected, due to the high level of homology among the three small Mafs. Nevertheless, further studies showed that these transcription factors have critical roles in various cellular processes, including stress signaling, hematopoiesis, CNS function and oncogenesis. Recent data provide a possible link between small Maf-mediated transcription and the inflammatory response.