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TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 21A; TTC21A

TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 21A; TTC21A

Alternative titles; symbolsSTRESS-INDUCIBLE PROTEIN 2; STI2INTRAFLAGELLAR TRANSPORT 139A; IFT139AHGNC Approved Gene Symbol: TTC21ACytogenetic location: 3p22.2 ...

Alternative titles; symbols

  • STRESS-INDUCIBLE PROTEIN 2; STI2
  • INTRAFLAGELLAR TRANSPORT 139A; IFT139A

HGNC Approved Gene Symbol: TTC21A

Cytogenetic location: 3p22.2 Genomic coordinates (GRCh38): 3:39,107,679-39,139,008 (from NCBI)

▼ Cloning and Expression
By database analysis to identify putative coding sequences in a region of chromosome 3 associated with carcinomas, Protopopov et al. (2003) identified TTC21A, which they called ST12. The deduced 1,320-amino acid protein contains 10 N-terminal tetratricopeptide repeats of about 34 amino acids each. Northern blot analysis detected strong expression of a 6.5-kb transcript in testis only.

Liu et al. (2019) published an image of immunohistochemical staining in human testicular tissue from the Human Protein Atlas, which demonstrated expression of TTC21A in preleptotene spermatocytes, pachytene spermatocytes, round spermatids, and elongated spermatids. The authors suggested that TTC21A may play an important role in spermatogenesis.

▼ Gene Structure
Protopopov et al. (2003) determined that the TTC21A gene contains 27 exons and spans about 27 kb.

▼ Mapping
Using FISH and a deletion cell hybrid panel, Protopopov et al. (2003) mapped the TTC21A gene to chromosome 3p21.3.

▼ Molecular Genetics
By whole-exome sequencing (WES) in 65 unrelated Han Chinese men with primary infertility due to multiple morphologic abnormalities of sperm flagella (MMAF), who were negative for mutations in known MMAF-associated genes, Liu et al. (2019) identified 3 men with homozygous or compound heterozygous mutations in the TTC21A gene (611430.0001-611430.0004); see spermatogenic failure-37 (SPGF37; 618429). The mutations were not found in 968 Han Chinese controls and segregated with disease in the family (A015) for which parental DNA was available. WES in another cohort of 167 men with primary infertility and MMAF revealed 2 unrelated Tunisian men who were homozygous for a TTC21A splice site mutation (611430.0005).

▼ Animal Model
Liu et al. (2019) found that mice with a c.2534del mutation in the Ttc21a gene had a significant reduction of Ttc21a expression in the testes compared to wildtype testes. Approximately 78% of homozygous mutant mice were infertile, whereas heterozygotes had fertility comparable to that of wildtype mice. Semen analysis in homozygous mutants showed spermatozoa with significantly reduced motility and progressive motility, and staining revealed morphologic abnormalities, primarily tailless spermatozoa with an abnormal head-tail junction, as well as short and coiled flagella. Transmission electron microscopy showed structural abnormalities of the connecting piece during spermiogenesis and multiple structural defects of the flagella, with a greatly increased percentage of flagella exhibiting abnormal principal pieces and end pieces compared to controls. Axonemal structural abnormalities, such as abnormal bulges, extra peripheral microtubule doublets, lack of central-pair microtubules, absent dynein arms, and abnormal arrangement of the 9 peripheral microtubule doubles, were also frequently observed.

▼ ALLELIC VARIANTS ( 5 Selected Examples):

.0001 SPERMATOGENIC FAILURE 37
TTC21A, IVS6DS, G-A, +1
In an infertile Han Chinese man with multiple morphologic abnormalities of sperm flagella (SPGF37; 618429), who was born to first-cousin parents (family A004), Liu et al. (2019) identified homozygosity for a splicing mutation (c.716+1G-A, NM_145755.2) in intron 6 of the TTC21A gene, predicted to result in an immediate premature termination codon (ile240-to-ter; I204X). The RT-PCR product obtained from the proband was longer than that of a control male individual, and sequencing showed partial retention of intron 6, which the authors suggested was due to use of a downstream cryptic splice donor site in intron 6. The mutation was not found in 968 Han Chinese controls, in the Han Chinese population of the 1000 Genomes Project, or in the East Asian population of the ExAC database. Familial segregation was not reported.

.0002 SPERMATOGENIC FAILURE 37
TTC21A, GLN777TER
In an infertile Han Chinese man (family A015) with multiple morphologic abnormalities of sperm flagella (SPGF37; 618429), Liu et al. (2019) identified compound heterozygosity for mutations in the TTC21A gene: a c.2329C-T transition (c.2329C-T, NM_145755.2), resulting in a gln777-to-ter (Q777X) substitution, and a c.341A-G transition, resulting in a tyr114-to-cys (Y114C; 611430.0003) substitution at a conserved residue within the cilia-related TPR domain. The proband's unaffected parents were each heterozygous for one of the mutations, neither of which was found in 968 Han Chinese controls or in the Han Chinese population of the 1000 Genomes Project. The Q777X mutation was not found in the East Asian population of the ExAC database, whereas Y114C mutation was present at low frequency (1.2 x 10(-4)).

.0003 SPERMATOGENIC FAILURE 37
TTC21A, TYR114CYS
For discussion of the c.341A-G transition (c.341A-G, NM_145755.2) in the TTC21A gene, resulting in a tyr114-to-cys (Y114C) substitution, that was found in compound heterozygous state in an infertile Han Chinese man with spermatogenic failure-37 (SPGF37; 618429) by Liu et al. (2019), see 611430.0002.

.0004 SPERMATOGENIC FAILURE 37
TTC21A, 1-BP DEL, 2563G
In an infertile Han Chinese man (family S022) with multiple morphologic abnormalities of sperm flagella (SPGF37; 618429), Liu et al. (2019) identified homozygosity for a 1-bp deletion (c.2563delG, NM_145755.2), causing a frameshift predicted to result in a premature termination codon (val855-to-ter; V855X). The mutation was not found in 968 Han Chinese controls, in the Han Chinese population of the 1000 Genomes Project, or in the East Asian population of the ExAC database. Familial segregation was not reported.

.0005 SPERMATOGENIC FAILURE 37
TTC21A, IVS23DS, G-T, +5
In 2 unrelated infertile Tunisian men (F001 and F002) with multiple morphologic abnormalities of sperm flagella (SPGF37; 618429), Liu et al. (2019) identified homozygosity for a splicing mutation (c.3116+5G-T, NM_145755.2) in intron 23 of the TTC21A gene. This variant had a frequency of 0.00058 in the gnomAD database. Analysis of total RNA extracted from patient sperm samples showed no signal for TTC21A, whereas amplification of a control sample yielded a good signal, consistent with mRNA decay in the patients.

Tags: 3p22.2