title: A common variant in combination with a nonsense mutation in a member of the thioredoxin family causes primary ciliary dyskinesia.
abstract: Thioredoxins belong to a large family of enzymatic proteins that function as general protein disulfide reductases, therefore participating in several cellular processes via redox-mediated reactions. So far, none of the 18 members of this family has been involved in human pathology. Here we identified TXNDC3, which encodes a thioredoxin-nucleoside diphosphate kinase, as a gene implicated in primary ciliary dyskinesia (PCD), a genetic condition characterized by chronic respiratory tract infections, left-right asymmetry randomization, and male infertility. We show that the disease, which segregates as a recessive trait, results from the unusual combination of the following two transallelic defects: a nonsense mutation and a common intronic variant found in 1% of control chromosomes. This variant affects the ratio of two physiological TXNDC3 transcripts: the full-length isoform and a novel isoform, TXNDC3d7, carrying an in-frame deletion of exon 7. In vivo and in vitro expression data unveiled the physiological importance of TXNDC3d7 (whose expression was reduced in the patient) and the corresponding protein that was shown to bind microtubules. PCD is known to result from defects of the axoneme, an organelle common to respiratory cilia, embryonic nodal cilia, and sperm flagella, containing dynein arms, with, to date, the implication of genes encoding dynein proteins. Our findings, which identify a another class of molecules involved in PCD, disclose the key role of TXNDC3 in ciliary function; they also point to an unusual mechanism underlying a Mendelian disorder, which is an SNP-induced modification of the ratio of two physiological isoforms generated by alternative splicing.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 654, F-94000 Créteil, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Duriez
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.forename: Estelle
authors.initials: E
authors.lastname: Escudier
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bridoux
authors.forename: Denise
authors.initials: D
authors.lastname: Escalier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rayet
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Marcos
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Vojtek
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bercher
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
mesh_terms: D018389:Codon, Nonsense / Q000235:genetics*; D017931:DNA Primers; D040461:Gene Components; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D007619:Kartagener Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013737:Testis / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D017931:DNA Primers; C452260:NME8 protein, human; D020033:Protein Isoforms; D013879:Thioredoxins