Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature

Abstract

FBXL3 (F-Box and Leucine Rich Repeat Protein 3) encodes a protein that contains an F-box and several tandem leucine-rich repeats (LRR) domains. FBXL3 is part of the SCF (Skp1-Cullin-F box protein) ubiquitin ligase complex that binds and leads to phosphorylation-dependent degradation of the central clock protein cryptochromes (CRY1 and CRY2) by the proteasome and its absence causes circadian phenotypes in mice and behavioral problems. No FBXL3-related phenotypes have been described in humans. By a combination of exome sequencing and homozygosity mapping, we analyzed two consanguineous families with intellectual disability and identified homozygous loss-of-function (LoF) variants in FBXL3. In the first family, from Pakistan, an FBXL3 frameshift variant [NM 012158.2:c.885delT:p.(Leu295Phefs * 25)] was the only

Druggable genome screen identifies new regulators of the abundance and toxicity of ATXN3, the Spinocerebellar Ataxia Type 3 disease protein

“…It remains, however, to be determined whether targeting FBXL3 will prove to be a viable therapeutic strategy in SCA3. On the one hand, null FBXL3 mutations cause autosomal recessive developmental delay and intellectual disability [61] suggesting that FBXL3 mediates the stability of numerous proteins and that complete loss of FBXL3 function is harmful for cells, at least during development. On the other hand, FBXL3 knockdown in our mammalian cell lines and in flies did not show accompanying toxicity (Supplementary Table 2 and Supplementary Figure 5).…”

Coupled network of the circadian clocks: a driving force of rhythmic physiology

“…3) [228,370,384,385,394,[399][400][401][402]. Genetic and molecular studies suggest that alterations in core clock components are associated with depression, bipolar disease, mood disorders, and intellectual disability [312,[403][404][405], as well as that chronic circadian misalignment may lead to reduced cognitive performance [406]. Additionally, clock disruption has been associated with cancer progression [217,407].…”

Integrative functional analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles

“…These include the autophagy-related ATG8 family members GABARAP, GABARAPL1, GABARAPL2, MAP1LC3B, and MAP1LC3C [9]. Moreover, a complementary approach implemented in The Search Tool for the Retrieval of Interacting Genes (STRING) identified three direct and ten indirect TECPR2 relationships, highlighting proteins whose dysfunction leads to TECPR2 deficiency-related phenotypes, including FBXL3 [51], ITCH [52], and ZFYVE26 [53]. These are depicted in Figure S3 and detailed in Table S6.…”