Primary Ciliary Dyskinesia-Causing Mutations in Amish and Mennonite Communities - 23/07/13
, Erik G. Puffenberger 2, Hauw Lie 1, Cynthia Helms 1, Kevin A. Strauss 2, Anne Bowcock 1, John L. Carson 3, Milan Hazucha 3, D. Holmes Morton 2, Anand C. Patel 1, Margaret W. Leigh 3, Michael R. Knowles 3, Maimoona A. Zariwala 3Abstract |
Objective |
To determine whether individuals with primary ciliary dyskinesia (PCD) from unrelated Amish and Mennonite families harbor a single and unique founder mutation.
Study design |
Subjects from Amish and Mennonite communities in several states were enrolled in the study. All subjects were clinically characterized, and nasal nitric oxide levels were measured. Nasal epithelial scrapings were collected from several subjects for ciliary ultrastructural analyses. DNA was isolated from patients with PCD and their unaffected first- and second-degree relatives. Genome-wide homozygosity mapping, linkage analyses, targeted mutation analyses, and exome sequencing were performed.
Results |
All subjects from Old-Order Amish communities from Pennsylvania were homozygous for a nonsense mutant DNAH5 allele, c.4348C>T (p.Q1450X). Two affected siblings from an unrelated Mennonite family in Arkansas were homozygous for the same nonsense DNAH5 mutation. Children with PCD from an Amish family from Wisconsin had biallelic DNAH5 mutations, c.4348C>T (p.Q1450X) and c.10815delT (p.P3606HfsX23), and mutations in other genes associated with PCD were also identified in this community.
Conclusion |
The Amish and Mennonite subjects from geographically dispersed and socially isolated communities had the same founder DNAH5 mutation, owing to the common heritage of these populations. However, disease-causing mutations in other PCD-associated genes were also found in affected individuals in these communities, illustrating the genetic heterogeneity in this consanguineous population.
Il testo completo di questo articolo è disponibile in PDF.Keyword : NO, PCD
Mappa
| Supported by the Children's Discovery Institute (to T.F.) and the National Institutes of Health (NIH; R21 HL082657 [to T.F.], R01 HL071798 [to M.K. and M.Z.], and U54 HL096458 [to T.F., J.C., M.L., M.K., and M.Z.]). The last grant supports Genetic Disorders of Mucociliary Clearance Consortium (part of NIH Rare Diseases Clinical Research Network), which receives programmatic support from the National Heart, Lung, and Blood Institute and the NIH Office of Rare Diseases Research. The views expressed do not necessarily reflect the official policies of the Department of Health and Human Services; mention of trade names, commercial practices, or organizations does not imply endorsement by the US government. The authors declare no conflicts of interest. |
Vol 163 - N° 2
P. 383-387 - agosto 2013 Ritorno al numero
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