By regulating the spatio-temporal expression of tissue-specific genes, MAF proteins act as key regulators of terminal differentiation in many tissues and organs, including bone, brain, kidney, lens, pancreas, and retina.40,41 While apparently no gross anomalies are associated with Maf haploinsufficiency in mice, Maf−/− pups die soon after birth and exhibit defective lens formation and eye development,17,18 chondrocyte terminal differentiation,21 as well as differentiation and function of mechanoreceptors and neurons with mechanosensory function.20,42 In contrast, a semi-dominant, missense mutation (c.881G>A, p.Arg291Gln) affecting the DNA-binding domain of Maf and causing a reduced transactivation activity of the transcription factor has been associated with congenital cataract in heterozygote mice,14 recapitulating the hypomorphic cataracts-associated MAF mutations in humans.13,30–33 Finally, a functionally distinct missense change (c.269A>T, p.Asp90Val) affecting the N-terminal transactivation domain and promoting enhanced transactivation function in Maf has been shown to cause a dominant isolated cataract phenotype.43 Contrary to these loss-of-function, gain-of-function, and haploinsufficiency models, we here showed a distinct, dominantly acting effect of MAF mutations underlying a complex developmental disorder affecting multiple organs and tissues. As such, the pleiotropic effect of impaired MAF phosphorylation in Aymé-Gripp syndrome expands the perturbing consequences of dysregulated MAF function for multiple developmental programs, establishing its role in morphogenesis, CNS development, hearing and growth, and delineates a novel instance of protein dosage effect in human disease.