TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition

Abstract

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant

Mechanism of ribosome-associated mRNA degradation during tubulin autoregulation

“…The methods and principles from the tubulin autoregulation pathway provide a roadmap to now dissect the analogous processes for ribosomal proteins and others. Mutations in TTC5 and the N-terminal recognition motif in a tubulin gene have previously been linked to neurodevelopmental defects 57,58 , hinting at physiologic role(s) for autoregulation. However, potential added roles for TTC5 in regulation of transcription and the actin cytoskeleton 59,60 , and putative consequences for tubulin structure complicated this interpretation.…”

Soluble αβ-tubulins reversibly sequester TTC5 to regulate tubulin mRNA decay

“…Mutations in TTC5 and SCAPER have also been implicated in neurodevelopmental disorders [16][17][18] , underscoring the broader importance of tubulin autoregulation in human physiology. Tubulin autoregulation is highly conserved amongst higher eukaryotes, operating in all cell types tested so far 24,[43][44][45][46][47] .…”

“…Mutations in TTC5 or SCAPER associated with complete or near-complete loss of protein have been linked to tubulinopathies-a class of neurodevelopmental disorders arising from mutations in tubulins [16][17][18][19][20][21] . Disruption of tubulin autoregulation in cultured cells compromises mitotic fidelity 14,15 , a phenotype frequently attributed to aberrant microtubule dynamics 22,23 .…”

Mechanism of ribosome-associated mRNA degradation during tubulin autoregulation

“…Mutations in TTC5 and the N-terminal recognition motif in a tubulin gene have previously been linked to neurodevelopmental defects, 62 , 63 hinting at physiologic role(s) for autoregulation. However, potential added roles for TTC5 in regulation of transcription and the actin cytoskeleton, 64 , 65 and putative consequences for tubulin structure complicated this interpretation.…”