MNS1 variant associated with situs inversus and male infertility

Leslie, Joseph S, Rawlins, Lettie E., Chioza, Barry A, Olubodon, Oluwaseun R., Salter, Claire, Fasham, James, Jones, Hannah, Cross, Harold E., Lam, Simon, Harlalka, V. Gaurav, Muggenthaler, Martina M.A., Crosby, Andrew H. and Baple, Emma L. (2019) MNS1 variant associated with situs inversus and male infertility. European Journal of Human Genetics, 28, 50-55. (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.

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Contributors

Author: Claire Salter

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