Loss-of-function mutations in QRICH2 cause male infertility with multiple morphological abnormalities of the sperm flagella

Nat Commun. 2019 Jan 25;10(1):433. doi: 10.1038/s41467-018-08182-x.


Aberrant sperm flagella impair sperm motility and cause male infertility, yet the genes which have been identified in multiple morphological abnormalities of the flagella (MMAF) can only explain the pathogenic mechanisms of MMAF in a small number of cases. Here, we identify and functionally characterize homozygous loss-of-function mutations of QRICH2 in two infertile males with MMAF from two consanguineous families. Remarkably, Qrich2 knock-out (KO) male mice constructed by CRISPR-Cas9 technology present MMAF phenotypes and sterility. To elucidate the mechanisms of Qrich2 functioning in sperm flagellar formation, we perform proteomic analysis on the testes of KO and wild-type mice. Furthermore, in vitro experiments indicate that QRICH2 is involved in sperm flagellar development through stabilizing and enhancing the expression of proteins related to flagellar development. Our findings strongly suggest that the genetic mutations of human QRICH2 can lead to male infertility with MMAF and that QRICH2 is essential for sperm flagellar formation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / deficiency
  • A Kinase Anchor Proteins / genetics
  • Adult
  • Animals
  • Calcium-Binding Proteins / deficiency
  • Calcium-Binding Proteins / genetics
  • Consanguinity
  • Gene Expression
  • Gene Expression Profiling
  • Heat-Shock Proteins / deficiency
  • Heat-Shock Proteins / genetics
  • Humans
  • Infertility, Male / genetics*
  • Infertility, Male / metabolism
  • Infertility, Male / pathology
  • Loss of Function Mutation*
  • Male
  • Mice
  • Mice, Knockout
  • Microtubule Proteins / genetics*
  • Pedigree
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Sperm Motility
  • Sperm Tail / metabolism*
  • Sperm Tail / pathology
  • Sperm Tail / ultrastructure
  • Testis / chemistry
  • Testis / metabolism
  • Whole Genome Sequencing


  • A Kinase Anchor Proteins
  • AKAP3 protein, human
  • CABYR protein, human
  • Calcium-Binding Proteins
  • Heat-Shock Proteins
  • Microtubule Proteins
  • ODF2 protein, human
  • Phosphoproteins
  • QRICH2 protein, human
  • Qrich2 protein, mouse