TOPORS as a novel causal gene for Joubert syndrome

Abstract

Joubert syndrome (JBTS) is a Mendelian disorder of the primary cilium defined by the clinical triad of hypotonia, developmental delay, and a distinct cerebellar malformation called the molar tooth sign. JBTS is inherited in an autosomal recessive, autosomal dominant, or X-linked recessive manner. Though over 40 genes have been identified as causal for JBTS, molecular diagnosis is not made in 30%-40% of individuals who meet clinical criteria. TOPORS encodes topoisomerase I-binding arginine/ serine-rich protein, and homozygosity for a TOPORS missense variant (c.29C > A; p. (Pro10Gln)) was identified in individuals with the ciliopathy oral-facial-digital syndrome in two families of Dominican descent. Here, we report an additional proband of Dominican ancestry with JBTS found by exome sequencing to be homozygous for the identical p.(Pro10Gln) TOPORS missense variant. Query of the Mount Sinai BioMe biobank, which includes 1880 individuals of Dominican ancestry, supports a high carrier frequency of the TOPORS p.(Pro10Gln) variant in individuals of Dominican descent. Our data nominates TOPORS as a novel causal gene for JBTS and suggests that TOPORS variants should be considered in the differential of ciliopathy-spectrum disease in individuals of Dominican ancestry.

Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS

“…However, this redundancy is likely limited. While RNF4 loss is embryonic lethal in mice (Hu et al, 2010 ), mutations in TOPORS are associated with a variant of retinitis pigmentosa (Chakarova et al, 2007 ) characterised by apoptotic rod cells, and with Joubert syndrome (Strong et al, 2023 ), a rare disease characterised by brain stem anomalies and in some cases retinal dystrophy. In fruit flies, TOPORS was observed to localise to dedicated nuclear compartments where it regulates the activity of chromatin insulator complexes (Capelson and Corces, 2005 ).…”

The dCMP deaminase DCTD and the E3 ligase TOPORS are central mediators of decitabine cytotoxicity

“…However, this redundancy is likely limited. While RNF4 loss is embryonic lethal in mice 59 , mutations in TOPORS are associated with a variant of retinitis pigmentosa 60 , characterised by apoptotic rod cells, and in Joubert syndrome 61 , a rare disease characterised by brain stem anomalies and in some cases retinal dystrophy. In fruit flies, TOPORS was observed to be localised to dedicated nuclear compartments where it regulates the activity of chromatin insulator complexes 62 .…”