Loss-of-Function Mutations in a Human Gene Related to Chlamydomonas reinhardtii Dynein IC78 Result in Primary Ciliary Dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a group of heterogeneous disorders of unknown origin, usually inherited as an autosomal recessive trait. Its phenotype is characterized by axonemal abnormalities of respiratory cilia and sperm tails leading to bronchiectasis and sinusitis, which are sometimes associated with situs inversus (Kartagener syndrome) and male sterility. The main ciliary defect in PCD is an absence of dynein arms. We have isolated the first gene involved in PCD, using a candidate-gene approach developed on the basis of documented abnormalities of immotile strains of Chlamydomonas reinhardtii, which carry axonemal ultrastructural defects reminiscent of PCD. Taking advantage of the evolutionary conservation of genes encoding axonemal proteins, we have isolated a human sequence (DNAI1) related to IC78, a C. reinhardtii gene encoding a dynein intermediate chain in which mutations are associated with the absence of outer dynein arms. DNAI1 is highly expressed in trachea and testis and is composed of 20 exons located at 9p13-p21. Two loss-of-function mutations of DNAI1 have been identified in a patient with PCD characterized by immotile respiratory cilia lacking outer dynein arms. In addition, we excluded linkage between this gene and similar PCD phenotypes in five other affected families, providing a clear demonstration of locus heterogeneity. These data reveal the critical role of DNAI1 in the development of human axonemal structures and open up new means for identification of additional genes involved in related developmental defects.

CATSPER2, a human autosomal nonsyndromic male infertility gene

“…7 DNAH11, encoding for axonemal heavy-chain dynein type 11, was the first PCD gene identified. 8,9 It was recently demonstrated that DNAH11 mutations account for situs inversus totalis but probably only for a minority of PCD cases. No gene involved in pure asthenospermia or asthenoteratozoospermia has been identified so far, although associations with mtDNA haplogroups 10 and an autosomal dominant gene 11 were reported.…”

Axonemal Beta Heavy Chain Dynein DNAH9: cDNA Sequence, Genomic Structure, and Investigation of Its Role in Primary Ciliary Dyskinesia

“…Genetic heterogeneity of PCD, previously proposed because of the complex architecture of cilia, has been demonstrated through linkage studies (Blouin et al, 2000;Witt et al, 1999;Meeks et al, 2000). Recently, mutations were found in an intermediate chain dynein gene, DNAI1, in one patient with PCD (Pennarun et al, 1999).…”

Diagnostic Methods in Primary Ciliary Dyskinesia

“…Since the first description of a gene causing PCD in 1999 [12], there has been an exponential increase in reports of PCD-associated genes. There are now over thirty known genes responsible for >60% of cases.…”

“…To date mutations have been identified in 6 genes encoding for proteins that are part of the ODA (DNAH5, DNAI1, DNAI2, DNAL1, NME8 (TXNDC3) and DNAH11) [12,[71][72][73][74][75]. Mutations in DNAH5 and DNAI1 are thought to account for the largest proportion of PCD patients: 30% and 9% respectively [19,[76][77][78][79].…”