The Mafb cleft‐associated variant H131Q is not required for palatogenesis in the mouse

Abstract

Background Orofacial clefts (OFCs) are common birth defects with complex etiology. Genome wide association studies for OFC have identified SNPs in and near MAFB. MAFB is a transcription factor critical for structural development of digits, kidneys, skin, and brain. MAFB is also expressed in the craniofacial region. Previous sequencing of MAFB in a Filipino population revealed a novel missense variant significantly associated with an increased risk for OFC. This MAFB variant, leading to the amino acid change H131Q, was knocked into the mouse Mafb, resulting in the MafbH131Q allele. The MafbH131Q construct was engineered to allow for deletion of Mafb (“Mafbdel”). Results Mafbdel/del animals died shortly after birth. Conversely, MafbH131Q/H131Q mice survived into adulthood at Mendelian ratios. Mafbdel/del and MafbH131Q/H131Q heads exhibited normal macroscopic and histological appearance at all embryonic time points evaluated. The periderm was intact based on expression of keratin 6, p63, and E‐cadherin. Despite no effect on craniofacial morphogenesis, H131Q inhibited the Mafb‐dependent promoter activation of Arhgap29 in palatal mesenchymal, but not ectodermal‐derived epithelial cells in a luciferase assay. Conclusions Mafb is dispensable for murine palatogenesis in vivo, and the cleft‐associated variant H131Q, despite its lack of morphogenic effect, altered the expression of Arhgap29 in a cell‐dependent context.

Ionic polyphosphorylation of histidine repeat proteins by inorganic polyphosphate

“…12 The 8-histidine repeat (H131-H138) of MafB is highly conserved in vertebrates, 44 and a missense mutation of the first residue in this repeat (H131Q) has been associated with orofacial clefts. 44,45 While we focused on proteins with long (≥ 5 consecutive) histidine stretches, the example of HRG suggests that iH-PPn may also occur on proteins with shorter interrupted histidine-rich regions, which could vastly expand the scope of target proteins.…”