A novel frameshift variant in AXDND1 may cause multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family.

Imtiaz ALI; Meng-Lei YANG; Fazal RAHIM; Haider ALI; Aurang ZEB; Nisar AHMAD; Yousaf RAZA; Wang YUE; Muhammad SHOAIB; Tanveer ABBAS; Wasim SHAH; Hui MA; Huan ZHANG; Hao YIN; Qing-Hua SHI

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A novel frameshift variant in AXDND1 may cause multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family.

Author: Imtiaz ALI ¹ ; Meng-Lei YANG ¹ ; Fazal RAHIM ¹ ; Haider ALI ¹ ; Aurang ZEB ¹ ; Nisar AHMAD ¹ ; Yousaf RAZA ¹ ; Wang YUE ¹ ; Muhammad SHOAIB ¹ ; Tanveer ABBAS ¹ ; Wasim SHAH ¹ ; Hui MA ¹ ; Huan ZHANG ¹ ; Hao YIN ² ; Qing-Hua SHI ¹
Author Information

1. Centre for Reproduction and Genetics, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Centre, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
2. Department of Molecular Biology, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
Publication Type:Case Reports
Keywords: AXDND1; MMAF; consanguineous family; frameshift mutation; male infertility
MeSH: Humans; Male; Sperm Tail/ultrastructure*; Frameshift Mutation; Infertility, Male/pathology*; Pakistan; Pedigree; Consanguinity; Axonemal Dyneins/genetics*; Adult; Spermatozoa; Exome Sequencing
From: Asian Journal of Andrology 2025;27(6):691-696
CountryChina
Language:English
Abstract: The syndrome of multiple morphological abnormalities of the sperm flagella (MMAF) is one of the most serious kinds of sperm defects, leading to asthenoteratozoospermia and male infertility. In this study, we use whole-exome sequencing to identify genetic factors that account for male infertility in a patient born from a consanguineous Pakistani couple. A homozygous frameshift mutation (c.1399_1402del; p.Gln468ArgfsTer2) in axonemal dynein light chain domain containing 1 ( AXDND1 ) was identified in the patient. Sanger sequencing data showed that the mutation was cosegregated recessively with male infertility in this family. Papanicolaou staining and scanning electron microscopy analysis of the sperm revealed severely abnormal flagellar morphology in the patient. Immunofluorescence and western blot showed undetectable AXDND1 expression in the sperm of the patient. Transmission electron microscopy analysis showed disorganized sperm axonemal structure in the patient, particularly missing the central pair of microtubules. Immunofluorescence staining showed the absence of sperm-associated antigen 6 (SPAG6) and dynein axonemal light intermediate chain 1 (DNALI1) signals in the sperm flagella of the patient. These findings indicate that AXDND1 is essential for the organization of flagellar axoneme and provide direct evidence that AXDND1 is a MMAF gene in humans, thus expanding the phenotypic spectrum of AXDND1 frameshift mutations.