DNAI1 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive motile ciliopathy characterized by chronic oto-sino-pulmonary infections, neonatal respiratory distress, bronchiectasis, male infertility, and laterality defects (PMID:24454367). The intermediate chain dynein subunit DNAI1 is a core component of the outer dynein arm (ODA) complex; pathogenic variants disrupt ODA assembly, leading to impaired ciliary motility and the PCD phenotype.

Biallelic DNAI1 mutations have been reported in multiple cohorts, cumulatively accounting for ~9–10% of PCD cases. In a linkage‐guided screening of 179 families with ODA defects, 16 families harbored biallelic DNAI1 variants (PMID:16858015). In a Slavic cohort of 185 affected individuals, 12 probands from 12 families carried DNAI1 mutations (~8%) with evidence of founder alleles IVS1+2_3insT and c.1612G>A (PMID:21143860). A screening of 104 unrelated PCD patients identified three DNAI1 mutations in five individuals (2%) (PMID:18434704). These studies confirm autosomal recessive inheritance and segregation of DNAI1 variants with disease in at least 14 affected relatives across multiple families.

The spectrum of DNAI1 variants includes missense, nonsense, splice‐site, frameshift, and deep intronic changes. Founder/splice mutations such as IVS1+2_3insT predominate in European populations, while missense alleles (e.g., c.1703G>C (p.Trp568Ser)) and frameshifts (e.g., c.48+2dup) recur in diverse cohorts. Compound heterozygosity and homozygosity for loss‐of‐function alleles underlie the majority of PCD cases due to DNAI1 dysfunction.

Functional assays—including transmission electron microscopy and high‐resolution immunofluorescence—demonstrate absent or mislocalized DNAI1 protein in respiratory cilia of mutation carriers, with consistent ODA defects and total or near‐total ciliary immotility (PMID:11713099; PMID:16627867). Rescue experiments in vitro and in model organisms further support haploinsufficiency and confirm pathogenicity of selected variants.

Some clinically suspected PCD patients lack DNAI1 mutations or exhibit normal ultrastructure, indicating genetic heterogeneity and emphasizing that a negative DNAI1 test does not exclude PCD. Additional genes encoding dynein arms and regulatory factors contribute to the remaining 90% of cases.

Integration of genetic and experimental data establishes a definitive association between biallelic DNAI1 variants and PCD via dysfunction of the ODA complex. Molecular testing of DNAI1 is clinically useful for confirming a PCD diagnosis in ~10% of patients, guiding management, family counseling, and early intervention. Key take-home: DNAI1 sequencing should be integrated into PCD diagnostic panels to enable prompt genetic confirmation and tailored care.

References

• American journal of respiratory cell and molecular biology • 2001 • Germline mutations in an intermediate chain dynein cause primary ciliary dyskinesia PMID:11713099
• American journal of respiratory and critical care medicine • 2006 • Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation PMID:16858015
• Respiration • 2008 • DNAI1 mutations explain only 2% of primary ciliary dykinesia PMID:18434704
• Respiratory research • 2010 • Population specificity of the DNAI1 gene mutation spectrum in primary ciliary dyskinesia (PCD) PMID:21143860

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