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PMID:23122589

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Citation

Kott, E, Duquesnoy, P, Copin, B, Legendre, M, Dastot-Le Moal, F, Montantin, G, Jeanson, L, Tamalet, A, Papon, JF, Siffroi, JP, Rives, N, Mitchell, V, de Blic, J, Coste, A, Clement, A, Escalier, D, Touré, A, Escudier, E and Amselem, S (2012) Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia. Am. J. Hum. Genet. 91:958-64

Abstract

Primary ciliary dyskinesia (PCD) is a group of autosomal-recessive disorders resulting from cilia and sperm-flagella defects, which lead to respiratory infections and male infertility. Most implicated genes encode structural proteins that participate in the composition of axonemal components, such as dynein arms (DAs), that are essential for ciliary and flagellar movements; they explain the pathology in fewer than half of the affected individuals. We undertook this study to further understand the pathogenesis of PCD due to the absence of both DAs. We identified, via homozygosity mapping, an early frameshift in LRRC6, a gene that encodes a leucine-rich-repeat (LRR)-containing protein. Subsequent analyses of this gene mainly expressed in testis and respiratory cells identified biallelic mutations in several independent individuals. The situs inversus observed in two of them supports a key role for LRRC6 in embryonic nodal cilia. Study of native LRRC6 in airway epithelial cells revealed that it localizes to the cytoplasm and within cilia, whereas it is absent from cells with loss-of-function mutations, in which DA protein markers are also missing. These results are consistent with the transmission-electron-microscopy data showing the absence of both DAs in cilia or flagella from individuals with LRRC6 mutations. In spite of structural and functional similarities between LRRC6 and DNAAF1, another LRR-containing protein involved in the same PCD phenotype, the two proteins are not redundant. The evolutionarily conserved LRRC6, therefore, emerges as an additional player in DA assembly, a process that is essential for proper axoneme building and that appears to be much more complex than was previously thought.

Links

PubMed PMC3487148 Online version:10.1016/j.ajhg.2012.10.003

Keywords

Alleles; Amino Acid Sequence; Axonemal Dyneins/genetics; Axonemal Dyneins/metabolism; Cilia/genetics; Cilia/pathology; Consanguinity; Consensus Sequence; Female; Fertility/genetics; Gene Order; Humans; Kartagener Syndrome/genetics; Kartagener Syndrome/metabolism; Male; Molecular Sequence Data; Mutation; Phenotype; Protein Transport; Proteins/chemistry; Proteins/genetics; Proteins/metabolism; Sequence Alignment; Sperm Tail/metabolism; Sperm Tail/pathology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TILB

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0007827)
  • part_of:(CL:0002368)

Seeded From UniProt

complete

HUMAN:TILB

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0007827)
  • part_of:(CL:0002368)

Seeded From UniProt

complete

HUMAN:TILB

involved_in

GO:0003341: cilium movement

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TILB

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0007827)
  • part_of:(CL:0002368)

Seeded From UniProt

complete

HUMAN:TILB

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0007827)
  • part_of:(CL:0002368)

Seeded From UniProt

complete

HUMAN:TILB

involved_in

GO:0030317: flagellated sperm motility

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TILB

involved_in

GO:0036158: outer dynein arm assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TILB

involved_in

GO:0036159: inner dynein arm assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TILB

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TILB

involved_in

GO:0060287: epithelial cilium movement involved in determination of left/right asymmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TILB

involved_in

GO:0061458: reproductive system development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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