• PMID: 31534215
• Gene Name: MNS1
• Condition: Male infertility
• Association: Associated
• Mutation: c.407_410del; p.(Glu136Glyfs*16)
• Population size: 1
• Population details: 1 family
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

MNS1 variant associated with situs inversus and male infertility

Leslie JS, Rawlins LE, Chioza BA, Olubodun OR, Salter CG, Fasham J, Jones HF, Cross HE, Lam S, Harlalka GV, Muggenthaler MMA, Crosby AH, Baple EL.

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. FAU - Leslie, Joseph S AU - Leslie JS AUID- ORCID: 0000-0003-0972-8818 AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. FAU - Rawlins, Lettie E AU - Rawlins LE AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. AD - Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital, Gladstone Road, Exeter, EX1 2ED, UK. FAU - Chioza, Barry A AU - Chioza BA AUID- ORCID: 0000-0002-3546-1726 AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. FAU - Olubodun, Oluwaseun R AU - Olubodun OR AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. FAU - Salter, Claire G AU - Salter CG AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. FAU - Fasham, James AU - Fasham J AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. AD - Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital, Gladstone Road, Exeter, EX1 2ED, UK. FAU - Jones, Hannah F AU - Jones HF AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. FAU - Cross, Harold E AU - Cross HE AD - Department of Ophthalmology, University of Arizona College of Medicine, Tucson, AZ, USA. FAU - Lam, Simon AU - Lam S AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. FAU - Harlalka, Gaurav V AU - Harlalka GV AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. FAU - Muggenthaler, Martina M A AU - Muggenthaler MMA AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. AD - Department of Cardiology, Royal Devon and Exeter NHS Foundation Trust (Wonford), Barrack Road, Exeter, EX2 5DW, UK. FAU - Crosby, Andrew H AU - Crosby AH AD - Institute of Biomedical and Clinical Science, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK. A.H.Crosby@exeter.ac.uk.