MNS1 variant associated with situs inversus and male infertility

Joseph S Leslie,Hannah F Jones,Harold E Cross,Emma L Baple,Barry A Chioza,Gaurav V Harlalka,Lettie E Rawlins,James Fasham,Claire G Salter,Simon Lam,Oluwaseun R Olubodun,Andrew H Crosby,Martina M A Muggenthaler

doi:10.1038/s41431-019-0489-z

Abstract

Ciliopathy disorders due to abnormalities of motile cilia encompass a range of autosomal recessive conditions typified by chronic otosinopulmonary disease, infertility, situs abnormalities and hydrocephalus. Using a combination of genome-wide SNP mapping and whole exome sequencing (WES), we investigated the genetic cause of a form of situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family, assuming that an autosomal recessive founder variant was responsible. This identified a single shared (2.34 Mb) region of autozygosity on chromosome 15q21.3 as the likely disease locus, in which we identified a single candidate biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)]. Genotyping of multiple family members identified randomisation of the laterality defects in other homozygous individuals, with all wild type or MNS1 c.407_410del heterozygous carriers being unaffected, consistent with an autosomal recessive mode of inheritance. This study identifies an MNS1 variant as a cause of laterality defects and male infertility in humans, mirroring findings in Mns1-deficient mice which also display male infertility and randomisation of left–right asymmetry of internal organs, confirming a crucial role for MNS1 in nodal cilia and sperm flagella formation and function.

Highlights

IntroductionCilia and flagella are highly conserved and important protuberances of the plasma membrane that perform a diverse range of functions in the human body
This variant NM_018365.2:c.407_410del; p.(Glu136Glyfs*16), Chr15:g.56446887_56446890del [hg38] in Meiosis specific nuclear structural 1 protein (MNS1), predicted to result in a frameshift and premature stop codon, was not listed in the Genome Aggregation Database, ClinVar, National Center for Biotechnology Information or the Human Gene Mutation Database (HGMDpro) and represented the only candidate shared variant genome-wide that could not be excluded on the basis of mode of inheritance or presence at high frequency in gnomAD (>2.5%)
All four individuals with situs inversus (SI) were confirmed to be homozygous for the MNS1 variant by dideoxy sequencing (Fig. 1c)

Summary

Introduction

Cilia and flagella are highly conserved and important protuberances of the plasma membrane that perform a diverse range of functions in the human body. Flagella are larger organelles that have a similar ultrastructure to cilia and function to propel spermatozoa. Motile cilia beat rhythmically to induce the movement of fluids, whereas non-motile or primary cilia functions in sensory perception and cell signalling [1]. Nodal cilia are expressed transiently during embryonic development in vertebrates and establish left–right laterality [2], the precise mechanisms that underlie this function remain poorly understood. Previous studies have directly correlated defective nodal cilia with situs abnormalities in mouse models [2, 3]

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Conclusion