{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T09:13:23Z","timestamp":1788599603583,"version":"build-2803163510"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>\n                    Biallelic variants in fibrous sheath-interacting protein 2 (\n                    <jats:italic toggle=\"yes\">FSIP2<\/jats:italic>\n                    ) gene are a known cause of multiple morphological abnormalities of the sperm flagella (MMAF). This study aimed to identify novel\n                    <jats:italic toggle=\"yes\">FSIP2<\/jats:italic>\n                    variants and evaluate their impact on sperm ultrastructure and intracytoplasmic sperm injection (ICSI) outcomes. Whole-exome sequencing (WES) was employed to screen a cohort of 92 MMAF patients, with candidate variants validated via Sanger sequencing and third-generation sequencing. We identified one homozygous variant in a proband from a consanguineous family and two pairs of compound heterozygous variants in two unrelated, non-consanguineous families. Routine semen analysis demonstrated markedly reduced motility across all probands. Detailed morphological and ultrastructural assessments using Papanicolaou staining, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) demonstrated that approximately 80.0% of spermatozoa exhibited pathological elongation of the mitochondrial sheath in the midpiece. Furthermore, 50.0%\u201370.0% of spermatozoa displayed fibrous sheath dysplasia or loss in the principal piece. Immunofluorescence assays and Western blotting confirmed that FSIP2 protein localization was disrupted, and the expression of key axonemal assembly factors was dysregulated. Notably, successful pregnancies were achieved via ICSI in the partners of two probands. This study expands the mutational spectrum of\n                    <jats:italic toggle=\"yes\">FSIP2<\/jats:italic>\n                    in both consanguineous and non-consanguineous populations. Ultrastructural abnormalities, such as mitochondrial sheath elongation and fibrous sheath disassembly, highlight\n                    <jats:italic toggle=\"yes\">FSIP2<\/jats:italic>\n                    \u2019s critical role in flagellar assembly. Clinical results further support ICSI as an effective therapeutic intervention for affected individuals.\n                  <\/jats:p>","DOI":"10.4103\/aja202611","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T08:00:16Z","timestamp":1779436816000},"page":"680-689","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Novel biallelic FSIP2 variants cause male infertility with multiple morphological abnormalities of sperm flagella in humans"],"prefix":"10.4103","volume":"28","author":[{"given":"Jie","family":"Yang","sequence":"first","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi\u2019an 710000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Ting","family":"He","sequence":"additional","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi\u2019an 710000, China"},{"name":"Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Nan","family":"Gu","sequence":"additional","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi\u2019an 710000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Xue","sequence":"additional","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi\u2019an 710000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi\u2019an 710000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, AmCare Genomics Lab, Guangzhou 510005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Qiao","sequence":"additional","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi\u2019an 710000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Jia","family":"Shi","sequence":"additional","affiliation":[{"name":"Reproductive Center, Northwest Women\u2019s and Children\u2019s Hospital, Xi\u2019an 710000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"R1-20260905","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41572-023-00459-w","article-title":"Male 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