Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD; MIM 242650) is an autosomal recessive disorder of ciliary dysfunction with extensive genetic heterogeneity. PCD is characterized by bronchiectasis and upper respiratory tract infections, and half of the patients with PCD have situs inversus (Kartagener syndrome). We characterized the transcript and the genomic organization of the axonemal heavy chain dynein type 11 (DNAH11) gene, the human homologue of murine Dnah11 or lrd, which is mutated in the iv/iv mouse model with situs inversus. To assess the role of DNAH11, which maps on chromosome 7p21, we searched for mutations in the 82 exons of this gene in a patient with situs inversus totalis, and probable Kartagener syndrome associated with paternal uniparental disomy of chromosome 7 (patUPD7). We identified a homozygous nonsense mutation (R2852X) in the DNAH11 gene. This patient is remarkable because he is also homozygous for the F508del allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Sequence analysis of the DNAH11 gene in an additional 6 selected PCD sibships that shared DNAH11 alleles revealed polymorphic variants and an R3004Q substitution in a conserved position that might be pathogenic. We conclude that mutations in the coding region of DNAH11 account for situs inversus totalis and probably a minority of cases of PCD.
Bartoloni
Lucia
L
Division of Medical Genetics, University of Geneva Medical School, and University Hospitals, 1211 Geneva 4, Switzerland.
Blouin
Jean-Louis
JL
Pan
Yanzhen
Y
Gehrig
Corinne
C
Maiti
Amit K
AK
Scamuffa
Nathalie
N
Rossier
Colette
C
Jorissen
Mark
M
Armengot
Miguel
M
Meeks
Maggie
M
Mitchison
Hannah M
HM
Chung
Eddie M K
EM
Delozier-Blanchet
Celia D
CD
Craigen
William J
WJ
Antonarakis
Stylianos E
SE
D056444:Axonemal Dyneins; D001483:Base Sequence; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D018076:DNA, Complementary; D004398:Dyneins / Q000235:genetics*; D006801:Humans; D007619:Kartagener Syndrome / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012857:Situs Inversus / Q000201:enzymology* / Q000235:genetics
D018076:DNA, Complementary; D056444:Axonemal Dyneins; C465433:DNAH11 protein, human; D004398:Dyneins