Homozygous Loss of Septin12, but not its Haploinsufficiency, Leads to Male Infertility and Fertilization Failure

Genetics and genomics play a role in the causation of various human diseases. A large number of human reproductive disorders also arise as a result of genetic and genomic abnormalities. Reproductive disorders associated with predominantly genetics and genomic abnormalities are infertility, early pregnancy loss, congenital malformations, difference or disorder of sex development and reproductive cancers. The genetic etiology of human reproductive disorders is increasing with improved molecular biology techniques such as DNA microarray and next-generation sequencing. Infertility is one of the significant areas of reproductive disorders where genetics/genomics plays a substantial role and may result from chromosomal, copy number variation, Yq & pseudo autosomal region microdeletion/microduplication, gene mutation (monogenic, oligogenic, polygenic), multifactorial, epigenetic, mitochondrial, etc. abnormalities. All idiopathic infertile couples should be screened for genetic disorders before assisted reproduction to prevent transmission, if any, in offspring. Pregnancy wastage in early pregnancy is very high (about 70%) and is mainly related to chromosome number, copy number variation, and some monogenic or epigenetic abnormalities. Therefore, all early pregnancy loss cases should also be tested for genetic causes. Congenital malformations are structural defects in embryo, fetus, or newborns and affect about 3% (major malformations) of all births. The malformations could be due to the abnormalities of chromosomes, copy number variation, monogenic, oligogenic, multifactorial, or environmental. Array CGH &/or NGS should be used as the first step to screen congenital malformations. Differences/disorder of sex development is a developmental defect in which the determination and/or differentiation of chromosomal, gonadal, or phenotypic/anatomic sex is abnormal. It is a common disorder and is primarily related to genetic abnormalities. Therefore, a precise diagnosis, mainly through an array CGH and/or NGS, is crucial for the proper management to prevent future psychosexual problems and another birth with the disorder. Cancer is a genomic disorder characterized by genomic instability (due to a defect in DNA repair mechanism), uncontrolled replication (due to lack of response to inhibitory factors/loss of contact inhibition), neo-angiogenesis, invasion and metastasis. All cancer cases should be investigated for genomic markers (both hereditary and somatic) for precise diagnosis, prognosis, and genetic counseling. In this review, we will try to evaluate the role of genetics and genomics in the above-mentioned reproductive disorders, along with genetic & genomic techniques used and reproductive counseling in addition to our experiences.

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“…Genetic defects of sperm leading to oocyte activation failure (fertilization failure) are PLCζ, SEPTIN12, etc genes. [123][124][125]…”

Section: Male Infertilitymentioning

confidence: 99%

The Genetic and Genomic Landscape of Human Reproductive Disorders: An Overview with Our Experience

Halder

Sharma²,

Rana³

et al. 2023

MRAJ

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Genetic etiological spectrum of sperm morphological abnormalities

Arora,

Mehta,

Sethi

et al. 2024

J Assist Reprod Genet

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Human spermatogenesis leads to a reduced nuclear pore structure and function

Santos,

Knowles,

Dendooven

et al. 2024

Preprint

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Nuclear pore complexes (NPCs) are nuclear gateways which regulate transit of molecules larger than 40kDa through a Ran-dependent transport. The somatic human NPC scaffold consists of three stacked rings: cytoplasmic, nucleoplasmic, and inner ring, which define an approximately 55nm-wide central channel. However, how NPC architecture accommodates the different function of non-somatic cells is largely unknown. Here, we reveal the in-cell architecture of the human sperm NPC exhibiting a central channel less than 40nm-wide, outlined exclusively by the inner ring. This is accompanied by a 6-fold reduction in nuclear diffusion and mis-localization of Ran-dependent transport components. We also unveil a septin filaments meshwork connecting the NPCs and postulate a mechanical role in channel constriction. Furthermore, we show the end of meiosis as the key differentiation step for NPC architectural changes. Our work uses an integrative approach comprising electron-cryo-tomography, super-resolution-light-microscopy and biochemistry, to investigate macromolecular structure/ function in human physiological contexts.

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Homozygous Loss of Septin12, but not its Haploinsufficiency, Leads to Male Infertility and Fertilization Failure

Cited by 4 publications

References 45 publications

The Genetic and Genomic Landscape of Human Reproductive Disorders: An Overview with Our Experience

The Genetic and Genomic Landscape of Human Reproductive Disorders: An Overview with Our Experience

Genetic etiological spectrum of sperm morphological abnormalities

Human spermatogenesis leads to a reduced nuclear pore structure and function

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