期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 189, 期 6, 页码 707-717出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201311-2047OC
关键词
cilia; Kartagener syndrome; ciliopathy; exome sequencing; RSPH1
资金
- NIH-ORDR-NHLBI [U54HL096458-06]
- NIH-NHLBI [5R01HL071798, 1R01HL117836, HHSN268201100037C.]
- NIH-NHGRI [U54HG006493]
- NIH-R01 [DK068306]
- Intramural Research Program of the NIH-NIAID
- NIH-NCATS [UL1TR000083]
- Chapel Hill [UL1TR000154]
- Cystic Fibrosis Foundation [CFF R026-CRO7, R026-CR11]
- NIH-NIDDK [P30-DK065988]
Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD. 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 (FEU, 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 degrees C), but an abnormal, circular beat pattern. Conclusions: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic imitations 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.
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