Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility
Abstract: The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly
- Location
-
Deutsche Nationalbibliothek Frankfurt am Main
- Extent
-
Online-Ressource
- Language
-
Englisch
- Notes
-
PLoS genetics. - 14, 8 (2018) , e1007602, ISSN: 1553-7404
- Event
-
Veröffentlichung
- (where)
-
Freiburg
- (who)
-
Universität
- (when)
-
2021
- Creator
- DOI
-
10.1371/journal.pgen.1007602
- URN
-
urn:nbn:de:bsz:25-freidok-1750392
- Rights
-
Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
-
15.08.2025, 7:26 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Ta-Shma, Asaf
- Hjeij, Rim
- Antony, Dinu
- Schmidts, Miriam
- Omran, Heymut
- Universität
Time of origin
- 2021
Other Objects (12)
Neph-Proteine interagieren mit dem Multiadapterprotein ZO-1
Recessive DNAH9 loss-of-function mutations cause laterality defects and subtle respiratory ciliary-beating defects
Mutations in the gene encoding IFT dynein complex component WDR34 cause jeune asphyxiating thoracic dystrophy
The many faces of congenital anomalies of the kidney and urinary tract
TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport
Ciliary dyneins and dynein related ciliopathies
Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement
De novo truncating NOVA2 variants affect alternative splicing and lead to heterogeneous neurodevelopmental phenotypes
Identification of a TPP1 Q278X mutation in an iranian patient with neuronal ceroid lipofuscinosis 2: literature review and mutations update
Clinical and neuroradiological spectrum of biallelic variants in NOTCH3
A homozygous deletion of exon 5 of KYNU resulting from a maternal chromosome 2 isodisomy (UPD2) causes Catel-Manzke-Syndrome/VCRL syndrome
IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans
Neph-Proteine interagieren mit dem Multiadapterprotein ZO-1
Recessive DNAH9 loss-of-function mutations cause laterality defects and subtle respiratory ciliary-beating defects
Mutations in the gene encoding IFT dynein complex component WDR34 cause jeune asphyxiating thoracic dystrophy
The many faces of congenital anomalies of the kidney and urinary tract
TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport
Ciliary dyneins and dynein related ciliopathies
Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement
De novo truncating NOVA2 variants affect alternative splicing and lead to heterogeneous neurodevelopmental phenotypes
Identification of a TPP1 Q278X mutation in an iranian patient with neuronal ceroid lipofuscinosis 2: literature review and mutations update
Clinical and neuroradiological spectrum of biallelic variants in NOTCH3
A homozygous deletion of exon 5 of KYNU resulting from a maternal chromosome 2 isodisomy (UPD2) causes Catel-Manzke-Syndrome/VCRL syndrome
IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans
Neph-Proteine interagieren mit dem Multiadapterprotein ZO-1
Recessive DNAH9 loss-of-function mutations cause laterality defects and subtle respiratory ciliary-beating defects
Mutations in the gene encoding IFT dynein complex component WDR34 cause jeune asphyxiating thoracic dystrophy
The many faces of congenital anomalies of the kidney and urinary tract
TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport
Ciliary dyneins and dynein related ciliopathies
Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement
De novo truncating NOVA2 variants affect alternative splicing and lead to heterogeneous neurodevelopmental phenotypes
Identification of a TPP1 Q278X mutation in an iranian patient with neuronal ceroid lipofuscinosis 2: literature review and mutations update
Clinical and neuroradiological spectrum of biallelic variants in NOTCH3
A homozygous deletion of exon 5 of KYNU resulting from a maternal chromosome 2 isodisomy (UPD2) causes Catel-Manzke-Syndrome/VCRL syndrome