title: Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused by DNAH11 mutations.
abstract: Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by perturbed or absent beating of motile cilia, which is referred to as Kartagener syndrome (KS) when associated with situs inversus. We present a German family in which five individuals have PCD and one has KS. PCD was confirmed by analysis of native and cultured respiratory ciliated epithelia with high-speed video microscopy. Respiratory ciliated cells from the affected individuals showed an abnormal nonflexible beating pattern with a reduced cilium bending capacity and a hyperkinetic beat. Interestingly, the axonemal ultrastructure of these respiratory cilia was normal and outer dynein arms were intact, as shown by electron microscopy and immunohistochemistry. Microsatellite analysis indicated genetic linkage to the dynein heavy chain DNAH11 on chromosome 7p21. All affected individuals carried the compound heterozygous DNAH11 mutations c.12384C>G and c.13552_13608del. Both mutations are located in the C-terminal domain and predict a truncated DNAH11 protein (p.Y4128X, p.A4518_A4523delinsQ). The mutations described here were not present in a cohort of 96 PCD patients. In conclusion, our findings support the view that DNAH11 mutations indeed cause PCD and KS, and that the reported DNAH11 nonsense mutations are associated with a normal axonemal ultrastructure and are compatible with normal male fertility.
authors.affiliation: Department for General Pediatrics, Charité University Hospital, Campus Virchow, Berlin, Germany. georg.schwabe@charite.de
authors.forename: Georg C
authors.initials: GC
authors.lastname: Schwabe
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Niki Tomas
authors.initials: NT
authors.lastname: Loges
authors.forename: Daniel
authors.initials: D
authors.lastname: Birker
authors.forename: Colette
authors.initials: C
authors.lastname: Rossier
authors.forename: Margherita M
authors.initials: MM
authors.lastname: de Santi
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Manfred
authors.initials: M
authors.lastname: Fliegauf
authors.forename: Mike
authors.initials: M
authors.lastname: Failly
authors.forename: Uta
authors.initials: U
authors.lastname: Liebers
authors.forename: Mirella
authors.initials: M
authors.lastname: Collura
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gaedicke
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wahn
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Blouin
authors.forename: Bodo
authors.initials: B
authors.lastname: Niggemann
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Lucia
authors.initials: L
authors.lastname: Bartoloni
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D056444:Axonemal Dyneins; D054468:Axoneme / Q000648:ultrastructure*; D002923:Cilia / Q000648:ultrastructure; D004398:Dyneins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D056444:Axonemal Dyneins; C465433:DNAH11 protein, human; C497507:DNAH5 protein, human; C430745:DNAH9 protein, human; D004398:Dyneins