ZMYND10 – Primary Ciliary Dyskinesia

ZMYND10 encodes a cytoplasmic zinc-finger protein essential for dynein arm preassembly in motile cilia and flagella. Primary ciliary dyskinesia (PCD; MONDO:0016575) is an autosomal recessive disorder characterized by recurrent respiratory infections, laterality defects and male infertility. Biallelic loss-of-function variants in ZMYND10 disrupt both outer and inner dynein arm assembly, leading to ciliary immotility and classic PCD features (PMID:23891471).

Autosomal recessive ZMYND10 mutations have been reported in multiple unrelated families. A single couple with Kartagener’s syndrome harbored a homozygous truncating ZMYND10 variant and presented dextrocardia and recurrent respiratory infections (PMID:29402277). In a Slavic cohort, two unrelated patients with PCD carried the founder frameshift c.367del (p.His123ThrfsTer16) in homozygous state (PMID:26824761). In an initial survey of 38 PCD families, six probands had biallelic ZMYND10 variants, confirming a 16% contribution in this series (PMID:23891469). Together these studies encompass nine probands from at least eight unrelated families.

The variant spectrum includes frameshift, nonsense and splice-site mutations. A recurrent hypomorphic missense allele p.Val16Gly yields partial dynein arm assembly with residual stiff ciliary beating. The most frequently observed pathogenic change in functional studies is c.383_384del (p.Glu128fs), causing nonsense-mediated decay and absence of dynein arms.

Functional analyses demonstrate loss of axonemal dynein arms by transmission electron microscopy and immunofluorescence in patient cilia. Zmynd10 knockdown in zebrafish and Drosophila produces ciliary paralysis, laterality defects and male sterility, all rescuable by wild-type but not mutant ZMYND10 expression (PMID:23891471). In vitro interaction assays show ZMYND10 forms a complex with LRRC6, necessary for dynein arm preassembly.

Together, genetic and experimental data support a loss-of-function mechanism for ZMYND10 in PCD. The breadth of independent probands, concordant segregation and robust animal models justify a Strong clinical validity classification. ZMYND10 testing should be included in diagnostic panels for PCD, with implications for genetic counseling and family planning.

References

• Reproductive Biology and Endocrinology • 2018 • Live birth after Laser Assisted Viability Assessment (LAVA) to detect pentoxifylline resistant ejaculated immotile spermatozoa during ICSI in a couple with male Kartagener's syndrome. PMID:29402277
• PloS One • 2016 • ZMYND10--Mutation Analysis in Slavic Patients with Primary Ciliary Dyskinesia. PMID:26824761
• American Journal of Human Genetics • 2013 • ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. PMID:23891469
• American Journal of Human Genetics • 2013 • Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia. PMID:23891471

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