Bratman Morag, S., Itzkovich, C., Kurolap, A., Shohat, M., Durr, A., de Sainte Agathe, J.M., Bertrand, J., Koifman, A., Alkelai, A., Shuldiner, A.R., Mory, A., Harel, T., Mor-Shaked, H., Shalata, A., Paperna, T., Baris Feldman, H., Kakun, R.R., Kornitzer, D., Salzberg, A., Weiss, K. (2025). A founder variant in TBCB is associated with global developmental delay, autism spectrum, and spastic paraparesis.  Genet Med 27(11): 101569.

FBrf0263791

Research paper

Hereditary spastic paraparesis (HSP) is a genetically diverse group of Mendelian disorders characterized by length-dependent axonal degeneration. Microtubule dysfunction is a known mechanism in HSP that impairs axonal dynamics. TBCB encodes tubulin-folding cofactor B (TBCB), which, along with TBCE, regulates αβ-heterodimer dynamics and neuronal axonal growth. Here, we describe a new form of complicated HSP caused by a founder variant in TBCB. Exome sequencing revealed a homozygous c.589T>A p.(Tyr197Asn) variant in TBCB in a cohort of 10 individuals assembled through genematching tools. Protein function was assessed using Saccharomyces cerevisiae ortholog ALF1, and a CRISPR-Cas9-generated homologous mutant in Drosophila melanogaster. TBCB expression and localization were examined in fibroblasts using western blot and immunofluorescence. Participants displayed late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum. TBCB protein levels were reduced in affected fibroblasts. The ALF1 mutant in yeast increased benomyl sensitivity, resembling a loss-of-function phenotype. In Drosophila melanogaster, the homologous mutant led to reduced survival and impaired climbing ability. We describe a novel neurodevelopmental disorder with spastic paraparesis and a high carrier rate in the Ashkenazi Jewish population. Our results indicate that TBCB has a vital role in the development of central nervous system and potentially in axonal function in humans.