Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia

Mitchison, Hannah M.; Schmidts, Miriam; Loges, Niki T.; Freshour, Judy; Dritsoula, Athina; Hirst, Robert A.; O’Callaghan, Christopher; Blau, Hannah; Dabbagh, Maha Al; Olbrich, Heike; Beales, Philip L.; Yagi, Toshiki; Mussaffi, Huda; Chung, Eddie M.K.; Omran, Heymut; Mitchell, David R.

doi:10.1038/ng.1106

Cited by 244 publications

(265 citation statements)

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“…Dysfunction in dynein heavy chain families is asso- ciated with primary ciliary dyskinesia, 26 which presents with respiratory infection, situs inversus, and sometimes hydrocephalus. Cases of primary ciliary dyskinesia-associated hydrocephalus in humans have previously been reported, although the causative mutations have not been identified.…”

Section: Discussionmentioning

confidence: 99%

Panventriculomegaly with a wide foramen of Magendie and large cisterna magna

Kageyama

Miyajima

Ogino

et al. 2016

JNS

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C ertain congenital anomalies of adult-onset hydrocephalus share clinical symptoms with idiopathic normal pressure hydrocephalus (iNPH), such as long-standing overt ventriculomegaly, aqueductal stenosis, 29 and Blake's pouch cyst. 8 However, no disease-associated gene mutations have been identified, including those responsible for these congenital diseases. Moreover, although L1CAM mutations can cause aqueductal stenosis, patients carrying these mutations have clinical features different from patients with NPH. obJective The authors' goal in this paper is to provide the first clinical, radiological, and genetic studies of panventriculomegaly (PaVM) defined by a wide foramen of Magendie and large cisterna magna. methods Clinical and brain imaging data from 28 PaVM patients (including 10 patients from 5 families) were retrospectively studied. Five children were included. In adult patients, the age at onset was 56.0 ± 16.7 years. Tetraventricular dilation, aqueductal opening with flow void on T2-weighted images, and a wide foramen of Magendie and large cisterna magna (wide cerebrospinal fluid space at the fourth ventricle outlet) were essential MRI findings for PaVM diagnosis. 3D fast asymmetrical spin echo sequences were used for visualization of cistern membranes. Time-spatial labeling inversion pulse examination was performed to analyze cerebrospinal fluid movement. Copy number variations were determined using high-resolution microarray and were validated by quantitative polymerase chain reaction with breakpoint sequencing. results Adult patients showed gait disturbance, urinary dysfunction, and cognitive dysfunction. Five infant patients exhibited macrocranium. Patients were divided into 2 subcategories, those with or without downward bulging third ventricular floors and membranous structures in the prepontine cistern. Patients with bulging floors were successfully treated with endoscopic third ventriculostomy. Genetic analysis revealed a deletion in DNAH14 that encodes a dynein heavy chain protein associated with motile cilia function, and which co-segregated with patients in a family without a downward bulging third ventricular floor. coNclusioNs Panventriculomegaly with a wide foramen of Magendie and a large cisterna magna may belong to a subtype of congenital hydrocephalus with familial accumulation, younger age at onset, and symptoms of normal pressure hydrocephalus. In addition, a family with PaVM has a gene mutation associated with dysfunction of motile cilia.

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Section: Discussionmentioning

confidence: 99%

Panventriculomegaly with a wide foramen of Magendie and large cisterna magna

Kageyama

Miyajima

Ogino

et al. 2016

JNS

View full text Add to dashboard Cite

show abstract

“…Mutations in dynein assembly factor, DNAAF3, induce primary cilia dyskinesia and disturbance of left-right asymmetry in mice. 38 In embryos with mutations of Noto, a transcription factor regulating cilia formation, left-right asymmetry of internal organs and expression of laterality markers is randomized. 39 The Notch ligand Dll1- …”

Section: Node Cell Monocilia Create Leftward "Nodal Flow" and Activatmentioning

confidence: 99%

Human Heterotaxy Syndrome

Shiraishi

Ichikawa

2012

Circ J

118

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“…All of these assembly factors function together in the assembly of ODAs, but are considered to have distinct roles in the process. In conjunction with studies in Chlamydomonas, DNAAF1/ODA7, DNAAF2/PF13, and DNAAF3/PF22 have been shown to function as a chaperone complex for proper folding of the dynein-HCs [128]. DYX1C1 (also named DNAAF4) is also an assembly factor for dynein.…”

Section: Cytoplasmic Assembly Of Axonemal Componentsmentioning

confidence: 84%