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DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population.
Fertil Steril. 2017 06; 107(6):1312-1318.e2.FS

Abstract

OBJECTIVE

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.

DESIGN

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.

SETTING

Not applicable.

PATIENT(S)

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.

INTERVENTIONS(S)

None.

RESULT(S)

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.

CONCLUSION(S)

These DNAH1 gene mutations may be associated with DFS and infertility in the Han population.

Authors+Show Affiliations

Center of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen City, People's Republic of China.Department of Reproductive Medicine, the First Hospital Affiliated to Nanjing Medical University, Nan Jing, People's Republic of China.Center of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen City, People's Republic of China.Center of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen City, People's Republic of China.Center of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen City, People's Republic of China.Center of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen City, People's Republic of China.Center of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen City, People's Republic of China.Center for Reproduction and Genetics, Suzhou Hospital Affiliated with Nanjing Medical University, Suzhou, People's Republic of China. Electronic address: 709633358@qq.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28577616

Citation

Sha, Yanwei, et al. "DNAH1 Gene Mutations and Their Potential Association With Dysplasia of the Sperm Fibrous Sheath and Infertility in the Han Chinese Population." Fertility and Sterility, vol. 107, no. 6, 2017, pp. 1312-1318.e2.
Sha Y, Yang X, Mei L, et al. DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population. Fertil Steril. 2017;107(6):1312-1318.e2.
Sha, Y., Yang, X., Mei, L., Ji, Z., Wang, X., Ding, L., Li, P., & Yang, S. (2017). DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population. Fertility and Sterility, 107(6), 1312-e2. https://doi.org/10.1016/j.fertnstert.2017.04.007
Sha Y, et al. DNAH1 Gene Mutations and Their Potential Association With Dysplasia of the Sperm Fibrous Sheath and Infertility in the Han Chinese Population. Fertil Steril. 2017;107(6):1312-1318.e2. PubMed PMID: 28577616.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population. AU - Sha,Yanwei, AU - Yang,Xiaoyu, AU - Mei,Libin, AU - Ji,Zhiyong, AU - Wang,Xu, AU - Ding,Lu, AU - Li,Ping, AU - Yang,Shenmin, PY - 2016/08/05/received PY - 2017/04/11/revised PY - 2017/04/11/accepted PY - 2017/6/5/entrez PY - 2017/6/5/pubmed PY - 2017/8/19/medline KW - DNAH1 KW - Han population KW - dysplasia of the sperm fibrous sheath KW - gene mutation KW - infertility SP - 1312 EP - 1318.e2 JF - Fertility and sterility JO - Fertil. Steril. VL - 107 IS - 6 N2 - OBJECTIVE: 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. DESIGN: 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. SETTING: Not applicable. PATIENT(S): 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. INTERVENTIONS(S): None. RESULT(S): 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. CONCLUSION(S): These DNAH1 gene mutations may be associated with DFS and infertility in the Han population. SN - 1556-5653 UR - https://www.unboundmedicine.com/medline/citation/28577616/DNAH1_gene_mutations_and_their_potential_association_with_dysplasia_of_the_sperm_fibrous_sheath_and_infertility_in_the_Han_Chinese_population_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0015-0282(17)30311-4 DB - PRIME DP - Unbound Medicine ER -