Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.
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Knowles Michael R, Ostrowski Lawrence E, Leigh Margaret W, Sears Patrick R, Davis Stephanie D, Wolf Whitney E, Hazucha Milan J, Carson Johnny L, Olivier Kenneth N, Sagel Scott D, Rosenfeld Margaret, Ferkol Thomas W, Dell Sharon D, Milla Carlos E, Randell Scott H, Yin Weining, Sannuti Aruna, Metjian Hilda M, Noone Peadar G, Noone Peter J, Olson Christina A, Patrone Michael V, Dang Hong, Lee Hye-Seung, Hurd Toby W, Gee Heon Yung, Otto Edgar A, Halbritter Jan, Kohl Stefan, Kircher Martin, Krischer Jeffrey, Bamshad Michael J, Nickerson Deborah A, Hildebrandt Friedhelm, Shendure Jay, Zariwala Maimoona A
Аннотация
OBJECTIVES: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD.
METHODS: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis.
MEASUREMENTS AND MAIN RESULTS: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 % predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 ± Hz at 25°C), but an abnormal, circular beat pattern.
CONCLUSIONS: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.