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Introduction

KAT6B is the closest paralog of KAT6A within the MYST family, sharing approximately 50% amino acid identity across their catalytic domains. The human KAT6B gene maps to chromosome 10q22 and encodes a protein of 2,073 amino acids. Like KAT6A, KAT6B assembles into tetrameric complexes with BRPF scaffold proteins together with ING4/5 and EAF6, directing histone H3K14 and H3K23 acetylation at target gene promoters and enhancers. Despite their structural similarity, KAT6A and KAT6B are not functionally redundant in vivo, as demonstrated by the distinct and non-overlapping phenotypes of their respective knockout mouse models [1].

Structure and Biochemistry

KAT6B contains the canonical MYST domain architecture including an N-terminal double PHD finger, a central catalytic domain with a C2HC zinc finger, and a C-terminal serine-rich region [1,2]. An important distinction between KAT6A and KAT6B is their relative affinities for different BRPF paralogs. KAT6B shows preferential interaction with BRPF1, and the BRPF1–KAT6B complex specifically targets H3K23 acetylation, a mark associated with enhancer activity and neuronal gene expression.

Role in Development

Early studies established KAT6B (then named Querkopf) as an essential regulator of cerebral cortex development in mice; loss of KAT6B causes severe defects in cortical neuron generation and self-renewal of neural stem cells [2]. Mouse embryos lacking Kat6b survive to birth but display severe skeletal and neurological abnormalities, including delayed ossification, limb defects, and profound hypotonia [2,3]. KAT6B sustains H3K14ac and H3K23ac at Hox gene loci and their upstream regulatory elements, and its loss disrupts the proliferation-to-differentiation transition in cortical progenitors, reducing the expression of transcription factors including TBR1, NEUROD2, and SATB2 [3].

KAT6B-Associated Human Syndromes

Heterozygous loss-of-function mutations in KAT6B cause two clinically overlapping syndromes identified by whole-exome sequencing [4,5]. Genitopatellar syndrome (GPS; OMIM #606170) is characterized by absent or hypoplastic patellae, urogenital abnormalities, corpus callosum agenesis, and severe intellectual disability. Say-Barber-Biesecker-Young-Simpson (SBBYSS) syndrome (OMIM #603736) shares some features but is distinguished by blepharophimosis, long thumbs and halluces, and a milder urogenital phenotype. Genotype–phenotype correlations suggest that truncating mutations in the C-terminal region tend to cause GPS, while N-terminal or central mutations more often result in SBBYSS [4, 5,6]. Over 100 individuals with KAT6B mutations have been reported, and management remains supportive.

KAT6B in Cancer

Recurrent somatic mutations in KAT6B are identified in endometrial carcinoma, colorectal cancer, and bladder cancer. KAT6B expression is reduced in several tumor types and correlates with better differentiation and improved prognosis, consistent with a tumor suppressive role. Chromosomal translocations involving KAT6B have not been reported as recurrent oncogenic drivers, in contrast to KAT6A.