Volume 107, Issue 6, Pages 1312–1318.e2
Yanwei Sha, M.D., Xiaoyu Yang, M.D., Libin Mei, Ph.D., Zhiyong Ji, M.D., Xu Wang, M.D., Lu Ding, M.D., Ping Li, M.D., Shenmin Yang, M.D.
To investigate dynein, axonemal, heavy chain 1 (DNAH1) gene mutations that may be associated with dysplasia of the sperm fibrous sheath (DFS) and infertility in the Han Chinese population.
Dysfunction of DNAH1 is known to cause multiple morphologic abnormalities of the flagella (MMAF), DFS, and infertility. Whole-exome sequencing was performed in DFS subjects and the healthy control subjects.
Twenty-one patients of Han ethnicity with primary infertility and diagnosed with asthenozoospermia and MMAF, but without primary ciliary dyskinesia. Fifty healthy men with normal fertility served as control subjects.
Main Outcome Measure(s)
Whole-exome sequencing, polymerase chain reaction and sequencing, pedigree analysis, Western blotting, and immunofluorescence assay.
A total of 17 mutations in the DNAH1 gene were identified in 12 of the 21 patients. These included one homozygous mutation at the splice site and 16 complex heterozygous mutations at the splice sites and exons. These mutations may cause deletion, replacement of amino acids in the peptide, or introduction of a stop codon in the coding sequence according to bioinformatic prediction. Of note, 52430998CCT>C deletion at exon 73, which may result in c.11726_11727del:p.P3909fs, was found in six patients, which suggests that this mutation may be an etiologic factor for MMAF. Although these DNAH1 gene mutations were found in Exome Aggregation Consortium (ExAC) databases, none were found in the Han healthy control subjects. The expression of DNAH1 protein in the sperm of patient P10, with 52409336C>T in exon 45 and 52430998CCT>C in exon 73 mutations, and patient P12, with 52402755A>G in exon 37 and 52428484G>T in exon 67 mutations, was missing or very weak compared with the sperm of healthy control subjects. The peptide phenotypes of 52409336C>T, 52402755A>G, and 52428484G>T were R2356W, nonsense, and E3544X, respectively. The sperm tails were short or coiled in P10 and P12 compared with healthy control subjects. Pedigree analysis supported the notion that the combination of DNAH1 gene mutations 52430998CCT>C and 52409336C>T and 52428484G>T alone were associated with MMAF.
These DNAH1 gene mutations may be associated with DFS and infertility in the Han population.