A Variant in Abhydrolase Domain Containing 14A (ABHD14A) and the Suspicion of Aminoacylase 1 (ACY1) Deficiency

Abstract

Aminoacylase 1 (ACY1) deficiency is a rare autosomal recessive inborn error of metabolism, characterised by accumulation of N-acetyl-l-amino acids in urine and highly variable clinical presentations. In contrast, the abhydrolase domain containing 14A (ABHD14A) has been suggested to play a role in various metabolic processes and may be linked to diseases, although its precise function remains unclear. Importantly, ABHD14A is known to form a read-through transcript with ACY1, indicating the possibility that variants in ABHD14A may influence ACY1-related phenotypes. Here, we report a patient with suspected ACY1 deficiency, carrying a heterozygous variant in the ACY1 gene (c.1178G>A) together with a variant in ABHD14A (c.95G>A). The aim of this study was to functionally assess ACY1 activity and to investigate whether the ABHD14A variant affects ACY1 expression or enzyme activity. To this end, ACY1 enzyme activity was measured in patient-derived lymphocytes, and overexpression experiments in HEK293 cells were performed to analyse ACY1 enzyme activity as well as mRNA and protein levels of the patient-specific variants. We show that the patient-derived variant in ABHD14A does not affect ACY1 expression or enzyme activity. In addition, our report provides the first experimental evidence that the ABHD14A–ACY1 read-through does not lead to a functional detectable protein, supporting the hypothesis of nonsense-mediated RNA decay.