Endosomal trafficking defects in patient cells with KIAA1109 biallelic variants

Abstract

The uncharacterized gene KIAA1109 has recently been associated with a congenital neurological malformation disorder that variably presents with arthrogryposis, craniofacial and/or cardiac abnormalities. We have identified two additional patients with compound heterozygous KIAA1109 variants presenting with the same neurological malformations. The mechanism whereby KIAA1109 loss of function causes this spectrum of disorders was the primary focus of our studies. We hypothesized that KIAA1109 function could be conserved relative to the fly gene tweek and examined endocytosis and endosome recycling in patient fibroblasts. Furthermore, we examined the structure of the cytoskeleton and cilia based on functional overlap with endocytosis and several known etiologies for neuronal migration disorders. Utilizing primary dermal fibroblasts from one patient and a healthy donor, we performed immunofluorescence and endocytosis assays to examine the endosomal, cytoskeletal, and ciliary cellular phenotypes. We found notable abnormalities in endosomal trafficking and endosome recycling pathways. We also observed changes in the actin cytoskeleton and cilia structural dynamics. We conclude that the function of KIAA1109 in humans may indeed overlap with the function of the Drosophila ortholog, resulting in perturbations to endosomal trafficking and the actin cytoskeleton. These alterations have ripple effects, altering many pathways that are critical for proper neuronal migration and embryonic development.

Rewiring phospholipid biosynthesis reveals robustness in membrane homeostasis and uncovers lipid regulatory players

“…Intriguingly, Csf1 homologues in higher organisms are implicated in lipid storage (lpd-3, C. elegans ) and endosomal trafficking ( tweek and KIA1109, D. melanogaster and H. Sapiens , respectively), consistent with a role in lipid transport. Mutations in KIA1109 are associated with the Alkuraya-Kučinskas syndrome, a severe neurological malformation disorder (McKay et al , 2003; Kane et al , 2019; Verstreken et al , 2009). Therefore, it will be important to understand whether and how Csf1 is involved in lipid transport.…”

Systematic Identification of Host Cell Regulators of Legionella pneumophila Pathogenesis Using a Genome-wide CRISPR Screen

“…Mutants of the Drosophila ortholog tweek have reduced phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ] at synapses, resulting in decreased Wiscott-Aldrich syndrome protein (WASP)-dependent actin polymerization and decreased synaptic vesicle recycling (Khuong et al, 2010;Verstreken et al, 2009). Recently, similar defects in endosomal recycling and changes in the actin cytoskeleton were shown in human primary fibroblasts from patients with biallelic variants in KIAA1109 (Kane et al, 2019). Because endocytic membrane recycling (Cox et al, 2000) and PI(4,5)P 2 accumulation at the phagocytic cup (Botelho et al, 2000) are both required for efficient phagocytosis, it is possible that KIAA1109 plays a similar role in regulating these processes in macrophages during phagocytosis.…”

Compound Heterozygous Variants in a Surviving Patient With Alkuraya-Kučinskas Syndrome: A New Case Report and a Review of the Literature

“…All patients had a global developmental delay from infancy and variable levels of intellectual disability. Besides, another two survival patients with severe phenotype were reported in 2019 (5). In 2020, Kumar et al described four other surviving patients from two related families, similar to the cases reported by Gueneau et al all of whom also suffered from global developmental delay and mild-to-severe intellectual disability (6).…”