TTC12 – Primary Ciliary Dyskinesia

The tetratricopeptide repeat–containing protein 12 (TTC12) is essential for cytoplasmic preassembly of outer and inner dynein arm complexes in motile cilia and flagella. Biallelic variants in TTC12 underlie autosomal recessive primary ciliary dyskinesia (Primary Ciliary Dyskinesia), a disorder marked by chronic respiratory infections, laterality defects, and male infertility due to impaired ciliary and sperm motility.

Genetic evidence includes four independent AR families with loss-of-function TTC12 mutations and a consanguineous patient harboring a homozygous missense change. In a multi-family study, four distinct loss-of-function variants in TTC12 were identified in four unrelated families presenting with PCD and male infertility (PMID:31978331). A separate case report described a novel homozygous missense c.1069C>T (p.Arg357Trp) in an infertile Pakistani man with severe oligoasthenoteratozoospermia and PCD (PMID:38992144).

The variant spectrum comprises four LoF alleles (including splice and nonsense) and one missense (c.1069C>T (p.Arg357Trp)). The homozygous p.Arg357Trp variant segregated with disease in a consanguineous pedigree; additional segregation data were not detailed.

Functional studies demonstrate that TTC12 deficiency reduces mRNA and protein levels in patient spermatozoa (RT-PCR, immunofluorescence) with disorganized axonemal structure on TEM and SEM (PMID:38992144). CRISPR-Cas9 knockout of TTC12 in human airway cells and depletion in Paramecium tetraurelia recapitulate dynein arm assembly defects (PMID:31978331). A zebrafish ttc12 morpholino model reproduces laterality and ciliary phenotypes consistent with human PCD (PMID:36273201).

These convergent genetic and experimental findings establish a strong autosomal recessive association between TTC12 and primary ciliary dyskinesia. The combination of multiple unrelated probands, biallelic LoF and missense variants, and concordant functional data supports robust clinical validity.

Key Take-home: TTC12 should be included in diagnostic gene panels for AR PCD and male infertility evaluation.

References

• Molecular genetics and genomics • 2024 • A novel homozygous missense TTC12 variant identified in an infertile Pakistani man with severe oligoasthenoteratozoospermia and primary ciliary dyskinesia. PMID:38992144
• American journal of human genetics • 2020 • TTC12 Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Unveil Distinct Dynein Assembly Mechanisms in Motile Cilia Versus Flagella. PMID:31978331
• Human genomics • 2022 • Biallelic mutations of TTC12 and TTC21B were identified in Chinese patients with multisystem ciliopathy syndromes. PMID:36273201

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