GAS8 – Primary Ciliary Dyskinesia

The gene GAS8 encodes a subunit of the Nexin-Dynein Regulatory Complex critical for motile cilia integrity. Biallelic loss-of-function variants in GAS8 cause autosomal recessive Primary Ciliary Dyskinesia, characterized by chronic respiratory infections, situs inversus, infertility, and in some cases retinal dystrophy.

Multiple unrelated probands harbor homozygous truncating deletions or nonsense variants. A 43-year-old Emirati woman with Stargardt-like retinal dystrophy was found to have a homozygous GAS8 deletion by whole exome sequencing (PMID:35736137). An 11-year-old girl with chronic rhinosinusitis and recurrent otitis media carried a homozygous nonsense variant c.927C>A (p.Arg334Ter) (PMID:38873586). A male with isolated asthenozoospermia exhibited a homozygous splice donor mutation with absent axonemal GAS8 staining (PMID:37950557).

In a multi-patient series, two individuals from distinct families presented with missense variants including c.1172C>T (p.Ala391Val), confirming pathogenicity through CRISPR/Cas9 knock-in in mice and rescue assays in Chlamydomonas (PMID:27472056).

An additional cohort study identified bi-allelic loss-of-function GAS8 mutations in PCD patients showing subtle ciliary beating defects by high-speed videomicroscopy and axonemal disorganization by transmission electron microscopy; immunofluorescence demonstrated mislocalization of the N-DRC subunit DRC3 (PMID:27120127).

Mechanistically, GAS8 deficiency results in nexin-dynein regulatory complex destabilization and axonemal misalignment leading to reduced ciliary motility. Concordant mouse knockout phenotypes and rescue experiments support a loss-of-function disease mechanism.

Together, over eight unrelated probands, comprehensive functional and animal model data, and consistent segregation establish a definitive gene–disease relationship. GAS8 variant screening is clinically actionable for diagnosis, carrier testing, and genetic counseling in PCD.

References

• Ophthalmic genetics • 2022 • A Stargardt disease-like phenotype in GAS8-related primary ciliary dyskinesia. PMID:35736137
• Frontiers in pediatrics • 2024 • A novel mutation in GAS8 gene associated with chronic rhinosinusitis with nasal polyposis in a case of primary ciliary dyskinesia: a case report. PMID:38873586
• Clinical genetics • 2024 • A splice donor variant of GAS8 induces structural disorganization of the axoneme in sperm flagella and leads to nonsyndromic male infertility. PMID:37950557
• PLoS genetics • 2016 • Mutation of Growth Arrest Specific 8 Reveals a Role in Motile Cilia Function and Human Disease. PMID:27472056
• Human mutation • 2016 • Mutations in GAS8, a Gene Encoding a Nexin-Dynein Regulatory Complex Subunit, Cause Primary Ciliary Dyskinesia with Axonemal Disorganization. PMID:27120127

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