Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF). J Med Genet 2019 Oct;56(10):678-684
Date
06/04/2019Pubmed ID
31151990DOI
10.1136/jmedgenet-2018-105952Scopus ID
2-s2.0-85066476900 (requires institutional sign-in at Scopus site) 58 CitationsAbstract
BACKGROUND: Multiple morphological abnormalities of the sperm flagella (MMAF) is a kind of severe teratozoospermia. Patients with the MMAF phenotype are infertile and present aberrant spermatozoa with absent, short, coiled, bent and/or irregular flagella. Mutations in several genes can explain approximately 30%-50% of MMAF cases and more genetic pathogenies need to be explored. SPEF2 was previously demonstrated to play an essential role in sperm tail development in mice and pig. Dysfunctional mutations in SPEF2 impair sperm motility and cause a short-tail phenotype in both animal models.
OBJECTIVE: Based on 42 patients with severe infertility and MMAF phenotype, we explored the new genetic cause of human MMAF phenotype.
METHODS AND RESULTS: By screening gene variants in 42 patients with MMAF using whole exome sequencing, we identified the c. 12delC, c. 1745-2A > G, c. 4102 G > T and c. 4323dupA mutations in the SPEF2 gene from two patients. Both of these mutations are rare and potentially deleterious. Transmission electron microscope (TEM) analysis showed a disrupted axonemal structure with mitochondrial sheath defects in the patients' spermatozoa. The SPEF2 protein level was significantly decreased in the spermatozoa of the patients revealed by Western blot (WB) and immunofluorescence (IF) analyses.
CONCLUSION: Our experimental findings indicate that loss-of-function mutations in the SPEF2 gene can cause the MMAF phenotype in human.
Author List
Liu W, Sha Y, Li Y, Mei L, Lin S, Huang X, Lu J, Ding L, Kong S, Lu ZAuthor
Ling Mei MD Associate Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Abnormalities, MultipleAxoneme
Cell Cycle Proteins
Humans
Infertility, Male
Loss of Function Mutation
Male
Phenotype
Sperm Motility
Sperm Tail
Spermatozoa
