Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations

Abstract Background Potassium channels are important for the structure and function of the spermatozoa. As a potassium transporter, the mSlo3 is essential for male fertility as Slo3 knockout male mice were infertile with the series of functional defects in sperm cells. However, no pathogenic variant has been detected in human SLO3 to date. Here we reported a human case with homozygous SLO3 mutation. The function of SLO3 in human sperm and the corresponding assisted reproductive strategy are also investigated. Methods We performed whole-exome sequencing analysis from a large cohort of 105 patients with asthenoteratozoospermia. The effects of the variant were investigated by quantitative RT-PCR, western blotting, and immunofluorescence assays using the patient spermatozoa. Sperm morphological and ultrastructural studies were conducted using haematoxylin and eosin staining, scanning and transmission electron microscopy. Results We identified a homozygous missense variant (c.1237A > T: p.Ile413Phe) in the sperm-specific SLO3 in one Chinese patient with male infertility. This SLO3 variant was rare in human control populations and predicted to be deleterious by multiple bioinformatic tools. Sperm from the individual harbouring the homozygous SLO3 variant exhibited severe morphological abnormalities, such as acrosome hypoplasia, disruption of the mitochondrial sheath, coiled tails, and motility defects. The levels of SLO3 mRNA and protein in spermatozoa from the affected individual were reduced. Furthermore, the acrosome reaction, mitochondrial membrane potential, and membrane potential during capacitation were also afflicted. The levels of acrosome marker glycoproteins and PLCζ1 as well as the mitochondrial sheath protein HSP60 and SLO3 auxiliary subunit LRRC52, were significantly reduced in the spermatozoa from the affected individual. The affected man was sterile due to acrosome and mitochondrial dysfunction; however, intra-cytoplasmic sperm injection successfully rescued this infertile condition. Conclusions SLO3 deficiency seriously impact acrosome formation, mitochondrial sheath assembly, and the function of K+ channels. Our findings provided clinical implications for the genetic and reproductive counselling of affected families.

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A novel missense variant of the GNAI3 gene and recognisable morphological characteristics of the mandibula in ARCND1

Journal of Human Genetics ◽

10.1038/s10038-021-00915-z ◽

2021 ◽

Author(s):

Kumiko Yanagi ◽

Noriko Morimoto ◽

Manami Iso ◽

Yukimi Abe ◽

Kohji Okamura ◽

...

Keyword(s):

Three Dimensional ◽

Morphological Characteristics ◽

Missense Variant ◽

Nucleotide Binding ◽

Sequencing Analysis ◽

Guanine Nucleotide ◽

Guanine Nucleotide Binding Protein ◽

Computer Tomography Scan ◽

Novel Variant ◽

Guanine Nucleotide Binding

AbstractAuriculocondylar syndrome (ARCND) is an autosomal monogenic disorder characterised by external ear abnormalities and micrognathia due to hypoplasia of the mandibular rami, condyle and coronoid process. Genetically, three subtypes of ARCND (ARCND1, ARCND2 and ARCND3) have been reported. To date, five pathogenic variants of GNAI3 have been reported in ARCND1 patients. Here, we report a novel variant of GNAI3 (NM_006496:c.807C>A:p.(Asn269Lys)) in a Japanese girl with micrognathia using trio-based whole exome sequencing analysis. The GNAI3 gene encodes a heterotrimeric guanine nucleotide-binding protein. The novel variant locates the guanine nucleotide-binding site, and the substitution was predicted to interfere with guanine nucleotide-binding by in silico structural analysis. Three-dimensional computer tomography scan, or cephalogram, displayed severely hypoplastic mandibular rami and fusion to the medial and lateral pterygoid plates, which have been recognised in other ARCND1 patients, but have not been described in ARCND2 and ARCND3, suggesting that these may be distinguishable features in ARCND1.

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A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

Acta Endocrinologica ◽

10.1530/eje-16-0968 ◽

2017 ◽

Vol 176 (5) ◽

pp. K9-K14 ◽

Cited By ~ 5

Author(s):

Sandrine Caburet ◽

Ronit Beck Fruchter ◽

Bérangère Legois ◽

Marc Fellous ◽

Stavit Shalev ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Polycystic Ovary ◽

Missense Variant ◽

Genetic Alterations ◽

Homozygous Mutation ◽

Gonadotropin Secretion ◽

Whole Exome ◽

A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

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Whole exome sequencing analysis identifies a missense variant in COL1A2 gene which causes osteogenesis imperfecta Type IV in a family from Saudi Arabia

Journal of Musculoskeletal Surgery and Research ◽

10.4103/jmsr.jmsr_26_17 ◽

2017 ◽

Vol 1 (2) ◽

pp. 33 ◽

Cited By ~ 1

Author(s):

Musharraf Jelani ◽

YaserM Alkhiary ◽

Anum Ramzan ◽

Muhammad Ilyas ◽

Ubaidullah Khan ◽

...

Keyword(s):

Saudi Arabia ◽

Osteogenesis Imperfecta ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Missense Variant ◽

Osteogenesis Imperfecta Type ◽

Sequencing Analysis ◽

Type Iv ◽

Whole Exome ◽

Col1a2 Gene

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Compound Heterozygous CHAT Gene Mutations of a Large Deletion and a Missense Variant in a Chinese Patient With Severe Congenital Myasthenic Syndrome With Episodic Apnea

Frontiers in Pharmacology ◽

10.3389/fphar.2019.00259 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Zhimei Liu ◽

Li Zhang ◽

Danmin Shen ◽

Changhong Ding ◽

Xinying Yang ◽

...

Keyword(s):

Gene Mutations ◽

Missense Variant ◽

Large Deletion ◽

Chinese Patient ◽

Congenital Myasthenic Syndrome ◽

Compound Heterozygous ◽

Myasthenic Syndrome

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A Missense Mutation (Tyr88 to Cys) in the Platelet Membrane Glycoprotein Ibβ Gene Affects GPIb/IX Complex Expression

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616058 ◽

2001 ◽

Vol 86 (11) ◽

pp. 1249-1256 ◽

Cited By ~ 22

Author(s):

Yumi Kurokawa ◽

Takehiko Kamijo ◽

Shinji Kunishima ◽

Dermot Kenny ◽

Kiyoshi Kitano ◽

...

Keyword(s):

Missense Mutation ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Platelet Glycoprotein ◽

Homozygous Mutation ◽

Sequencing Analysis ◽

Giant Platelets ◽

Giant Platelet ◽

Negative Effect ◽

Dna Sequencing Analysis

SummaryThis study examined the molecular basis of a missense mutation of the platelet glycoprotein (GP) Ibβ gene in two families. In the propositus with a novel form of Bernard-Soulier syndrome (BSS) from Family I, only GPIbα was detectable in reduced amounts on platelet surfaces by flow cytometry. There were no GPIX or GPIbβ found by immunoblotting. DNA sequencing analysis showed a homozygous mutation in the GPIbβ gene which changed Tyr (TAC) to Cys (TGC) at residue 88. Her parents were heterozygous for Tyr88Cys in the GPIbβ gene. In transient transfection studies on 293T cells, both Tyr88Cys and Tyr88Ala mutations suppressed the expression of GPIb/IX complexes. In addition, Tyr88Cys GPIbβ mutation was found to exert a dominant negative effect on the GPIb expression.Five individuals from Family II, four of whom reported elsewhere as having giant platelet disorders with normal aggregation (BLOOD, 1997; 89: 2404) and one newly analyzed in this study, were heterozygous for Tyr88Cys in the GPIb gene. Microsatellite analysis of chromosome 22 showed a common haplotype in 8 of the individuals with Tyr88Cys mutations in Families I and II. Tyr88 in the GPIbβ gene plays a significant role in the GPIb/IX expression; the defect causes BSS in a homozygous form and possibly giant platelets in a heterozygous form.

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