
Genetic testing for Stickler syndrome does not reliably inform the optimal timing for providing prophylactic retinal treatment to reduce the risk of contralateral retinal detachment.


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Gene testing does inform diagnosis, but it can't tell doctors when to intervene with prophylactic retinal treatments.

Retinal Detachment Still Sticky Issue for Stickler Syndrome

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Genetic Testing Fails to Predict Optimal Timing for Retinal Detachment Prophylaxis in Stickler Syndrome


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DNAH3 は精子鞭毛の発達に不可欠であり、その欠損は精子運動性の低下と形態異常を引き起こす。


Axonemal protein complexes, including the outer and inner dynein arms (ODA/IDA), are highly ordered structures of the sperm flagella that drive sperm motility. Deficiencies in several axonemal proteins have been associated with male infertility, which is characterized by asthenozoospermia or asthenoteratozoospermia. Dynein axonemal heavy chain 3 (DNAH3) resides in the IDA and is highly expressed in the testis. However, the relationship between DNAH3 and male infertility is still unclear. Herein, we identified biallelic variants of DNAH3 in four unrelated Han Chinese infertile men with asthenoteratozoospermia through whole-exome sequencing (WES). These variants contributed to deficient DNAH3 expression in the patients’ sperm flagella. Importantly, the patients represented the anomalous sperm flagellar morphology, and the flagellar ultrastructure was severely disrupted. Intriguingly, Dnah3 knockout (KO) male mice were also infertile, especially showing the severe reduction in sperm movement with the abnormal IDA and mitochondrion structure. Mechanically, nonfunctional DNAH3 expression resulted in decreased expression of IDA-associated proteins in the spermatozoa flagella of patients and KO mice, including DNAH1, DNAH6, and DNALI1, the deletion of which has been involved in disruption of sperm motility. Moreover, the infertility of patients with DNAH3 variants and Dnah3 KO mice could be rescued by intracytoplasmic sperm injection (ICSI) treatment. Our findings indicated that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and may further contribute to the diagnosis, genetic counseling, and prognosis of male infertility.

### Competing Interest Statement

The authors have declared no competing interest.

Biallelic pathogenic variants in DNAH3 cause male infertility in humans and mice

ヒトとマウスにおける-dnah3-の両アレル性病原性変異が男性不妊を引き起こす


ヒトとマウスにおける DNAH3 の両アレル性病原性変異が男性不妊を引き起こす



Huntington's disease, an inherited neurodegenerative disorder, causes progressive motor, cognitive, and psychiatric symptoms in a 51-year-old woman, requiring comprehensive clinical evaluation and genetic testing for diagnosis and management.


Dr Karen E. Anderson provides a brief guide to the diagnosis, evaluation, and management of Huntington disease.

Progressive Motor, Cognitive Decline in 51-Year-Old Woman

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Genetic Disorder Causing Progressive Motor and Cognitive Decline in Middle-Aged Woman



Disruption of the full-length BEND2 protein leads to reduced primordial follicle pool, impaired oocyte quality, and accelerated decline in female fertility in mice.


Reproductive aging, characterized by a decline in female reproductive potential, is a significant biomedical challenge. A key factor in reproductive aging is the depletion of the ovarian reserve, the pool of primordial follicles in the ovary. Recent studies have implicated BEND2, a BEN domain-containing protein family member, in mammalian spermatogenesis. In the testis, Bend2 expresses two protein isoforms: full-length and truncated. Ablation of both proteins results in an arrested spermatogenesis. Because the Bend2 locus is on the X chromosome, and the Bend2-/y mutants are sterile, Bend2 ’s role in oogenesis remained elusive.

In this study, we employed a novel Bend2 mutation that completely blocks the expression of the full-length BEND2 protein but allows the expression of the truncated BEND2 isoform. However, this mutation does not confer male sterility, allowing us to investigate BEND2’s role in mice’s oocyte quality, follicular dynamics, and fertility. Our findings demonstrate that full-length BEND2 is dispensable for male fertility, and its ablation leads to impaired oocyte quality, reduced follicular formation, and an accelerated decline in fertility. These results reveal a critical role for BEND2 in oogenesis and provide insights into the mechanisms underlying reproductive aging. Furthermore, these findings hold relevance for the diagnostic landscape of human infertility.

### Competing Interest Statement

The authors have declared no competing interest.

BEND2 is a crucial player in oogenesis and reproductive aging

disruption-of-bend2-leads-to-impaired-oogenesis-and-accelerated-reproductive-aging-in-mice


Disruption of BEND2 Leads to Impaired Oogenesis and Accelerated Reproductive Aging in Mice



Hereditary transthyretin amyloidosis is a complex, progressive, and potentially fatal genetic disorder caused by mutations in the TTR gene, leading to the accumulation of amyloid deposits in various organs, with significant impact on patient quality of life. However, recent advancements in diagnostic approaches and therapeutic options provide new hope for improved management and outcomes.


The heterogeneity of hereditary amyloidosis can delay diagnosis and seriously affect prognosis and patient quality of life; these five things are need-to-know.

Hereditary Amyloidosis: 5 Things to Know

hereditary-transthyretin-amyloidosis-challenges-advancements-and-improving-patient-outcomes


Hereditary Transthyretin Amyloidosis: Challenges, Advancements, and Improving Patient Outcomes



Transgenerational genetic effects, if they exist at all, are extremely rare in mammals under naturally occurring genetic variation and are unlikely to contribute significantly to phenotypic variance.


Transgenerational genetic effects are defined as the effects of untransmitted parental alleles on the phenotype of their offspring. Well-known transgenerational genetic effects, in humans and other mammals, are the effects of a parental genotype on the nurturing ability of the parents, coined “genetic nurture”. However, there exist examples of transgenerational genetic effects in model organisms that are independent of nurturing effects and support the epigenetic transmission of a memory of the parental genotype possibly mediated by small RNA species. To test whether such transgenerational epigenetic effects might exist in mammals, we generated 833 isogenic C57BL/6J (B6) mice that differed only by the presence in the genome of their sire of one copy of four A/J chromosomes (MMU 15, 17, 19 or X). We measured 25 anatomical traits and performed RNA-Seq on five distinct tissues (heart, liver, pituitary, whole embryo, and placenta). There was no evidence of a significant effect from untransmitted A/J sire chromosome alleles, whether on anatomical traits or gene expression level. We observed an effect on Mid1 expression levels in multiple tissues, but this was shown to be due to a de novo mutation that occurred in one of the sire lines. We conclude that transgenerational epigenetic memory of non-transmitted paternal alleles - if it exists - is uncommon in mice and likely other mammals.

### Competing Interest Statement

The authors have declared no competing interest.

Lack of evidence supporting transgenerational effects of non-transmitted paternal alleles on the murine transcriptome

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Lack of Evidence Supporting Transgenerational Effects of Non-Transmitted Paternal Alleles on the Murine Transcriptome



New genetic risk factors for Alzheimer's disease have been identified in Ashkenazi Jews, potentially leading to novel therapeutic targets.


Researchers have identified new genetic variations that seem to be unique to Ashkenazi Jews, possibly paving the way for novel therapeutic targets.

Novel Alzheimer's Genes Unique to Ashkenazi Jews?

novel-genetic-risk-factors-for-alzheimer-s-in-ashkenazi-jews


Novel Genetic Risk Factors for Alzheimer's in Ashkenazi Jews



Early moderate prenatal alcohol exposure can lead to site-specific DNA methylation changes in newborns, impacting gene regulation without causing immediate behavioral effects.


Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in new-born pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.

### Competing Interest Statement

The authors have declared no competing interest.

The influence of early moderate prenatal alcohol exposure and maternal diet on offspring DNA methylation: a cross-species study

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The Impact of Prenatal Alcohol Exposure on Offspring DNA Methylation



Subtelomeric X- and Y’-elements are non-essential for telomere regulation and maintenance in yeast.


Telomeres, which are chromosomal end structures, play a crucial role in maintaining genome stability and integrity in eukaryotes. In the baker’s yeast Saccharomyces cerevisiae , the X-and Y’-elements are subtelomeric repetitive sequences found in all thirty-two and seventeen telomeres, respectively. While the Y’-elements serve as a backup for telomere functions in cells lacking telomerase, the function of the X-elements remains unclear. This study utilized the S. cerevisiae strain SY12, which has three chromosomes and six telomeres, to investigate the role of X-elements (as well as Y’-elements) in telomere maintenance. Deletion of Y’-elements (SY12YΔ), X-elements (SY12XYΔ+Y), or both X- and Y’-elements (SY12XYΔ) did not impact the length of the terminal TG1-3 tracks or telomere silencing. However, inactivation of telomerase in SY12YΔ, SY12XYΔ+Y, and SY12XYΔ cells resulted in cellular senescence and the generation of survivors. These survivors either maintained their telomeres through homologous recombination-dependent TG1-3 track elongation or underwent microhomology-mediated intra-chromosomal end-to-end joining. Our findings indicate the non-essential role of subtelomeric X-and Y’-elements in telomere regulation in both telomerase-proficient and telomerase-null cells and suggest that these elements may represent remnants of S. cerevisiae genome evolution. Furthermore, strains with fewer or no subtelomeric elements exhibit more concise telomere structures and offer potential models for future studies in telomere biology.

### Competing Interest Statement

The authors have declared no competing interest.

Elimination of subtelomeric repeat sequences exerts little effect on telomere essential functions in Saccharomyces cerevisiae

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Impact of Subtelomeric Repeat Deletion on Telomere Functions in Yeast



Epistasis facilitates the evolution of new functions by expanding the network of functional sequences and shortening evolutionary paths.


A protein’s genetic architecture – the set of causal rules by which its sequence produces its functions – also determines its possible evolutionary trajectories. Prior research has proposed that genetic architecture of proteins is very complex, with pervasive epistatic interactions that constrain evolution and make function difficult to predict from sequence. Most of this work has analyzed only the direct paths between two proteins of interest – excluding the vast majority of possible genotypes and evolutionary trajectories – and has considered only a single protein function, leaving unaddressed the genetic architecture of functional specificity and its impact on the evolution of new functions. Here we develop a new method based on ordinal logistic regression to directly characterize the global genetic determinants of multiple protein functions from 20-state combinatorial deep mutational scanning (DMS) experiments. We use it to dissect the genetic architecture and evolution of a transcription factor’s specificity for DNA, using data from a combinatorial DMS of an ancient steroid hormone receptor’s capacity to activate transcription from two biologically relevant DNA elements. We show that the genetic architecture of DNA recognition consists of a dense set of main and pairwise effects that involve virtually every possible amino acid state in the protein-DNA interface, but higher-order epistasis plays only a tiny role. Pairwise interactions enlarge the set of functional sequences and are the primary determinants of specificity for different DNA elements. They also massively expand the number of opportunities for single-residue mutations to switch specificity from one DNA target to another. By bringing variants with different functions close together in sequence space, pairwise epistasis therefore facilitates rather than constrains the evolution of new functions.

### Competing Interest Statement

The authors have declared no competing interest.

Epistasis facilitates functional evolution in an ancient transcription factor

epistasis-and-functional-evolution-in-a-transcription-factor


Epistasis and Functional Evolution in a Transcription Factor
