Sumathipala D. et al
Bi-allelic pathogenic variants in ZBTB11 have been associated with Intellectual Developmental Disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We expand the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions. We also describe combined malonic and methylmalonic aciduria (CMAMMA) as a biochemical manifestation. Since ZBTB11 encodes for a transcriptional regulator, we performed Chromatin immunoprecipitation (ChIP)-sequencing targeting ZBTB11 in fibroblasts from patients and controls. ChIP-seq reveals binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 shows reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. The majority of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts reveals dysregulation of mitochondrial functions. In addition, we uncover that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining CMAMMA. Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.
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