Case report: KPTN gene-related syndrome associated with a spectrum of neurodevelopmental anomalies including severe epilepsy

Abstract

Biallelic variants in the kaptin gene KPTN were identified recently in individuals with a novel syndrome referred to as autosomal recessive intellectual developmental disorder 41 (MRT41). MRT41 is characterized by developmental delay, predominantly in language development, behavioral abnormalities, and epilepsy. Only about 15 affected individuals have been described in the literature, all with primary or secondary macrocephaly. Using exome sequencing, we identified three different biallelic variants in KPTN in five affected individuals from three unrelated families. In total, two KPTN variants were already reported as a loss of function variants. A novel splice site variant in KPTN was detected in two unrelated families of this study. The core phenotype with neurodevelopment delay was present in all patients. However, macrocephaly was not present in at least one patient. In total, two patients exhibited developmental and epileptic encephalopathies with generalized tonic-clonic seizures that were drug-resistant in one of them. Thus, we further delineate the KPTN-related syndrome, especially emphasizing the severity of epilepsy phenotypes and difficulties in treatment in patients of our cohort.

The actin-associated protein Kaptin modulates F-actin barbed-end dynamics

“…In recent years, several lines of evidence have suggested a role for KPTN in neurodevelopment. Various mutations associated with the KPTN gene have been linked to neurodevelopmental delays, intellectual disability, seizure, macrocephaly, and epilepsy (Baple et al, 2014; Pajusalu et al, 2015; Thiffault et al, 2018; Miguez et al, 2020; Horn et al, 2023; Ullah et al, 2022; Levitin et al, 2023). Recently, the KICSTOR complex, composed of KPTN, ITFG2, C12orf66, and SZT2 was unveiled, which regulates the mTORC1 pathway (Wolfson et al, 2017).…”

“…Studies with mammalian Coronin have identified a conserved amino acid residue (Arg 30 ) within the N-terminal β-propeller region which when mutated to aspartic acid (R30D) reduced the actin filament binding activity (Cai et al, 2007). Alignment of vertebrate Coronin and KPTN protein sequence identified hKPTN Arg 59 to be equivalent to Arg 30 of Coronin (Fig. S6).…”