Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia

Horani, Amjad; Druley, Todd E.; Zariwala, Maimoona A.; Patel, Anand C.; Levinson, Benjamin T.; Arendonk, Laura G. Van; Thornton, Katherine C.; Giacalone, Joseph; Albee, Alison J.; Wilson, Kate; Turner, Emily H.; Nickerson, Deborah A.; Shendure, Jay; Bayly, Philip V.; Leigh, Margaret W.; Knowles, Michael R.; Brody, Steven L.; Dutcher, Susan K.; Ferkol, Thomas

doi:10.1016/j.ajhg.2012.08.022

Cited by 160 publications

(157 citation statements)

References 44 publications

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“…Of the 164 participants in the definite PCD group with two mutations in an associated PCD gene, 128 had two loss-of-function mutations, 28 had a loss-of-function mutation with either a missense variant or an in-frame deletion fulfilling criteria for pathogenic mutations, and 8 had missense mutations on both alleles fulfilling criteria for pathogenic mutations based on the previous reports (20)(21)(22). Molecular analysis of the 26 genes was performed for 174 of the 187 participants in the other/undefined group.…”

Section: Participantsmentioning

confidence: 99%

Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents

et al. 2016

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Rationale: Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations.Objectives: To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents.

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Section: Participantsmentioning

confidence: 99%

Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents

et al. 2016

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“…For nNO validation studies at six (non-UNC) sites, PCD was confirmed by PCD-specific ciliary EM defects and, by the presence of biallelic mutations in PCD genes (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Informed consent was obtained at the University of North Carolina at Chapel Hill and collaborating institutions under the auspices of Committees on the Protection of the Rights of Human Subjects.…”

Section: Original Researchmentioning

confidence: 99%

Standardizing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia

Leigh¹,

Hazucha²,

Chawla³

et al. 2013

Annals ATS

241

289

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Rationale: Several studies suggest that nasal nitric oxide (nNO) measurement could be a test for primary ciliary dyskinesia (PCD), but the procedure and interpretation have not been standardized.Objectives: To use a standard protocol for measuring nNO to establish a diseasespecific cutoff value at one site, and then validate at six other sites.Methods: At the lead site, nNO was prospectively measured in individuals later confirmed to have PCD by ciliary ultrastructural defects (n = 143) or DNAH11 mutations (n = 6); and in 78 healthy and 146 disease control subjects, including individuals with asthma (n = 37), cystic fibrosis (n = 77), and chronic obstructive pulmonary disease (n = 32). A disease-specific cutoff value was determined, using generalized estimating equations (GEEs). Six other sites prospectively measured nNO in 155 consecutive individuals enrolled for evaluation for possible PCD. Measurements and Main Results:At the lead site, nNO values in PCD (mean 6 standard deviation, 20.7 6 24.1 nl/min; range, 1.5-207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 6 118.8; 125.5-867.0 nl/min), asthma (267.8 6 103.2; 125.0-589.7 nl/min), or chronic obstructive pulmonary disease (223.7 6 87.1; 109.7-449.1 nl/min); however, there was overlap with cystic fibrosis (134.0 6 73.5; 15.6-386.1 nl/min). The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, .0.999). At six other sites, this cutoff identified 70 of the 71 (98.6%) participants with confirmed PCD.Conclusions: Using a standardized protocol in multicenter studies, nNO measurement accurately identifies individuals with PCD, and supports its usefulness as a test to support the clinical diagnosis of PCD.

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“…PCD is a group of rare human genetic diseases characterized by recurrent infections of the respiratory system, male infertility, and frequently laterality defects, all of which are tightly linked to cilia motility abnormalities. Up to now, 19 PCD genes have been identified (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, combined they account for about 50% of all PCD cases, suggesting the existence of multiple additional causative genes.…”

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confidence: 99%

Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility

Lei

Yuan

Cao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Primary ciliary dyskinesia (PCD) is an autosomal recessive disease caused by defective cilia motility. The identified PCD genes account for about half of PCD incidences and the underlying mechanisms remain poorly understood. We demonstrate that Reptin/ Ruvbl2, a protein known to be involved in epigenetic and transcriptional regulation, is essential for cilia motility in zebrafish. We further show that Reptin directly interacts with the PCD protein Lrrc6/Seahorse and this interaction is critical for the in vivo function of Lrrc6/Seahorse in zebrafish. Moreover, whereas the expression levels of multiple dynein arm components remain unchanged or become elevated, the density of axonemal dynein arms is reduced in reptin hi2394 mutants. Furthermore, Reptin is highly enriched in the cytosol and colocalizes with Lrrc6/Seahorse. Combined, these results suggest that the Reptin-Lrrc6/Seahorse complex is involved in dynein arm formation. We also show that although the DNA damage response is induced in reptin hi2394 mutants, it remains unchanged in cilia biogenesis mutants and lrrc6/seahorse mutants, suggesting that increased DNA damage response is not intrinsic to ciliary defects and that in vertebrate development, Reptin functions in multiple processes, both cilia specific and cilia independent.ciliopathy | chromatin remodeling complex | dynein arm assembly factor A lthough the sensory function of the cilium has garnered significant attention only in the past decade, defective cilia motility was recognized nearly four decades ago as the cause of primary (genetic) ciliary dyskinesia (PCD) (1). PCD is a group of rare human genetic diseases characterized by recurrent infections of the respiratory system, male infertility, and frequently laterality defects, all of which are tightly linked to cilia motility abnormalities. Up to now, 19 PCD genes have been identified (2-20). However, combined they account for about 50% of all PCD cases, suggesting the existence of multiple additional causative genes. Despite such significant advances, our understanding of how cilia motility is regulated is limited and the list of genes involved in cilia motility remains incomplete.In motile cilia or flagella, dynein arms are large protein complexes powering cilia motility. Not surprisingly, multiple PCD genes encode dynein arm components, including DNAL1, DNAI1, DNAI2, DNAH5, and DNAH11 (2-6). In addition, it is understood that dynein arm subunits are preassembled in the cytosol, transported into cilia/flagellum, and docked onto the axoneme, although the underlying mechanisms are poorly understood (21). In recent years, three PCD genes, i.e., DNAAF1/LRRC50 (7, 8), DNAAF2/ KTU (9), and DNAAF3/PF22 (10) have been shown to be involved in the assembly of dynein arm subunits, highlighting the relevance and importance of this process in cilia motility and PCD.Very recently, mutations in human LRRC6/SEAHORSE were linked to PCD (18). Similar to the three known dynein arm assembly factors, mutations in LRRC6/SEAHORSE lead to the absence of both the outer...

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Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia

Cited by 160 publications

References 44 publications

Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents

Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents

Standardizing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia

Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility

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