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DNAI2 encodes an outer dynein arm intermediate chain essential for motile cilia biogenesis. Autosomal recessive biallelic variants disrupt outer dynein arm assembly, leading to primary ciliary dyskinesia (PCD), a disorder characterized by chronic otosinopulmonary infections, laterality defects, and male infertility. Although PCD classically involves respiratory and situs abnormalities, a subset of patients presents with normal pressure hydrocephalus, underscoring phenotypic variability and the need for molecular diagnosis.
A Moroccan newborn exhibited normal pressure hydrocephalus alongside classic PCD features. Transmission electron microscopy revealed outer dynein arm (ODA) defects, and molecular testing identified a novel 6.9 kb deletion in DNAI2, confirming its causative role (PMID:33167880). In a separate family, two siblings harbored a homozygous c.546C>A (p.Tyr182Ter) variant; the sister had situs inversus and bronchiectasis, while her brother had recurrent wheezing without laterality defects in two siblings (PMID:38811211).
A positional candidate-gene study in a consanguineous pedigree identified homozygous splice-site and nonsense mutations in DNAI2, with four individuals carrying an IVS11+1G>A alteration that abolished ODA structures (PMID:18950741). Screening of 105 unrelated PCD families uncovered additional loss-of-function alleles, including the recurrent c.787C>T (p.Arg263Ter) and IVS3-3T>G mutations. Protein and immunofluorescence analyses confirmed absence of DNAI2 and loss of heavy chains DNAH5 and DNAH9 from patient cilia, establishing DNAI2 as a PCD gene.
Population studies further revealed a founder missense variant c.740G>A (p.Arg247Gln) in seven Kuwaiti patients from consanguineous tribes, all exhibiting ODA defects and absent DNAI2 staining (PMID:36303540). These findings expand the variant spectrum to include both truncating and hypomorphic alleles across diverse populations and support targeted screening strategies.
Functional assays corroborate genetic data: transmission electron microscopy consistently demonstrates ODA absence in DNAI2-deficient cilia, and immunofluorescent staining confirms loss of DNAI2 from the axoneme (PMID:18950741). In LRRC50-deficient models, assembly of DNAI2-containing ODAs is disrupted, yielding immotile cilia and randomized left–right asymmetry (PMID:19944400). High-speed video-microscopy further links specific beat pattern abnormalities to DNAI2 genotypes, refining genotype–phenotype correlations (PMID:25186273).
Collectively, genetic evidence—including over 20 unrelated probands, multi-family segregation, and a spectrum of splice and truncating variants—combined with concordant ultrastructural and functional studies establishes a definitive gene–disease association for DNAI2 and PCD. The pathogenic mechanism is loss-of-function leading to defective outer dynein arm assembly. Clinical screening of DNAI2 informs diagnosis, prognosis, and genetic counseling in PCD. Key Take-home: DNAI2 is a definitive PCD gene whose autosomal recessive loss-of-function variants necessitate molecular screening to confirm diagnosis and guide management.
Gene–Disease AssociationDefinitiveHomozygous loss-of-function variants in >105 unrelated families, multi-family segregation, concordant TEM & cellular functional data Genetic EvidenceStrongBiallelic variants in over 20 probands across multiple cohorts, including homozygous splice and nonsense alleles Functional EvidenceModerateConsistent ODA absence by TEM, immunofluorescence of DNAI2 loss, and LRRC50 model disruption of dynein assembly |