Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility

PLoS Genetics
Asaf Ta-ShmaHeymut Omran

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-...Continue Reading

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Citations

Sep 20, 2019·European Journal of Human Genetics : EJHG·Joseph S LeslieEmma L Baple
Dec 28, 2019·Journal of Medical Genetics·Mahmoud R FassadHannah M Mitchison
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Feb 8, 2022·Journal of Cellular Physiology·Tao Qiu, Sudipto Roy

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Methods Mentioned

BETA
exome sequencing
X-ray
light microscopy
co-immunoprecipitation
two-hybrid
Y2H
transmission electron microscopy
tandem affinity purification
two hybrid
Co-IP

Software Mentioned

Adobe Creative Suite
AxioVision
gnomAD
ALLEGRO29
PedCheck
Adobe Photoshop
DNAnexus
Adobe
AceView

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