Clinical, biochemical and cell biological characterization of KIDAR syndrome associated with a novel AP1B1 variant

Adaptor protein (AP) complexes play key roles in escorting transmembrane proteins to various intracellular destinations, including the trans-Golgi compartment, secretory vesicles, and the plasma membrane. The AP-1 complex is heterotetrametric, comprised of four individual subunits: β1, γ1, σ1, and μ1, and encoded by separate genes that interact selectively with distinct cargo proteins. When AP-1 complex assembly is impaired due to loss-of-function variants in any of its component genes, clinical consequences related to altered transmembrane protein trafficking may result. Biallelic pathogenic variants in the β1 subunit (AP1B1) are associated with a unique clinical phenotype including keratitis, ichthyosis, and deafness with autosomal recessive inheritance, the KIDAR syndrome. This disorder is further characterized by enteropathy, failure to thrive, neurodevelopmental delays, endocrinopathies, and abnormalities in copper (Cu) metabolism, the latter reflecting impact on intracellular trafficking of two transmembrane Cu-transporting ATPases, ATP7A and ATP7B. Ten individuals with KIDAR syndrome have been reported to date. Here we describe the clinical, biochemical, and cell biological effects associated with a novel homozygous AP1B1 variant, (NM_001127.4: c.667delC, p.Leu223Trp*fsTer38) in a previously unreported individual. Our findings expand the phenotypic spectrum of this rare inherited illness, provide new data related to its cell biological effects, and offer insights relevant to potential treatment.