RSPH1 – Primary Ciliary Dyskinesia

Primary Ciliary Dyskinesia (PCD) is an autosomal recessive disorder of motile cilia characterized by recurrent respiratory infections and varying ultrastructural defects. RSPH1 encodes a radial spoke head protein whose deficiency leads to central complex and radial spoke assembly defects. The first report identified a homozygous splice-site mutation in an affected sib-pair and, upon screening 413 probands, found biallelic loss-of-function variants in nine additional unrelated individuals, plus five affected siblings ([PMID:24568568]).

Genetic analyses across multiple cohorts have established RSPH1 as a PCD gene. In a consanguineous individual with central complex defects, homozygosity mapping and exome sequencing revealed a nonsense variant, and subsequent screening showed biallelic RSPH1 mutations in 10 of 48 families with central complex phenotypes ([PMID:23993197]). A targeted NGS panel further detected RSPH1 loss-of-function variants in four individuals from two unrelated families. Quantitative high-speed video-microscopy in 75 PCD patients demonstrated a characteristic circular beat pattern with preserved beat frequency in cases of central complex defects, including those with RSPH1 mutations ([PMID:31772028]). Immunofluorescence in 21 individuals confirmed absence of RSPH1 from mutant cilia and loss of spoke-head assembly ([PMID:25789548]).

Biallelic RSPH1 variants are predominantly loss-of-function: splice-site (e.g., c.275-2A>C), frameshift, and nonsense changes. A recurrent truncating allele, c.85G>T (p.Glu29Ter), has been reported in multiple unrelated families. No hypomorphic or deep-intronic RSPH1 variants have been described to date.

Functional studies demonstrate that wild-type RSPH1 localizes to ciliary axonemes, and its loss prevents assembly of spoke-head components RSPH4A and RSPH9, destabilizing the central microtubule complex. High-speed videomicroscopy reveals a preserved beat frequency (≈6 Hz at 25 °C) but an abnormal circular stroke, consistent across loss-of-function alleles ([PMID:23993197], [PMID:24568568]).

Clinically, individuals with RSPH1 mutations exhibit a milder PCD phenotype: higher nasal nitric oxide levels (98.3 vs 20.7 nl/min; P < 0.0003), lower prevalence of neonatal respiratory distress (8 of 16), later onset of daily wet cough, and better FEV₁ compared with matched PCD controls. These features define a unique genotype-phenotype correlation and suggest residual ciliary function despite radial spoke head defects.

References

• American journal of respiratory and critical care medicine • 2014 • Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. PMID:24568568
• American journal of human genetics • 2013 • Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. PMID:23993197
• Journal of medical genetics • 2020 • Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia. PMID:31772028
• American journal of respiratory cell and molecular biology • 2015 • Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects. PMID:25789548

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