Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.

Purpose: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.

Methods: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.

Single-cell proteo-genomic reveals a comprehensive map of centrosome-associated spliceosome components.

Ribonucleoprotein (RNP) condensates are crucial for controlling RNA metabolism and splicing events in animal cells. We used spatial proteomics and transcriptomic to elucidate RNP interaction networks at the centrosome, the main microtubule-organizing center in animal cells. We found a number of cell-type specific centrosome-associated spliceosome interactions localized in subcellular structures involved in nuclear division and ciliogenesis.

Proteome balance in ciliopathies: the OFD1 protein example.

The balance of protein synthesis and degradation is finely regulated and influences cellular homeostasis and biological processes (e.g., embryonic development and neuronal plasticity).

OFD1: One gene, several disorders.

The OFD1 protein is necessary for the formation of primary cilia and left-right asymmetry establishment but additional functions have also been ascribed to this multitask protein. When mutated, this protein results in a variety of phenotypes ranging from multiorgan involvement, such as OFD type I (OFDI) and Joubert syndromes (JBS10), and Primary ciliary dyskinesia (PCD), to the engagement of single tissues such as in the case of retinitis pigmentosa (RP23). The inheritance pattern of these condition differs from X-linked dominant male-lethal (OFDI) to X-linked recessive (JBS10, PCD, and RP23).