Identification of a novel MYO1D variant associated with laterality defects,congenital heart diseases,and sperm defects in humans

The establishment of left–right asymmetry is a fundamental process in animal development.Interference with this process leads to a range of disorders collectively known as laterality defects,which manifest as abnormal arrangements of visceral organs.Among patients with laterality defects,congenital heart diseases(CHD)are prevalent.Through multiple model organisms,extant research has established that myosin-Id(MYO1D)deficiency causes laterality defects.This study investigated over a hundred cases and identified a novel biallelic variant of MYO1D(NM_015194:c.1531G>A;p.D511N)in a consanguineous family with complex CHD and laterality defects.Further examination of the proband revealed asthenoteratozoospermia and shortened sperm.Afterward,the effects of the D511N variant and another known MYO1D variant(NM_015194:c.2293C>T;p.P765S)were assessed.The assessment showed that both enhance the interaction withβ-actin and SPAG6.Overall,this study revealed the genetic heterogeneity of this rare disease and found that MYO1D variants are correlated with laterality defects and CHD in humans.Furthermore,this research established a connection between sperm defects and MYO1D variants.It offers guidance for exploring infertility and reproductive health concerns.The findings provide a critical basis for advancing personalized medicine and genetic counseling.

RNA modification in cardiovascular disease: implications for therapeutic interventions

Cardiovascular disease(CVD)is the leading cause of death in the world,with a high incidence and a youth-oriented tendency.RNA modification is ubiquitous and indispensable in cell,maintaining cell homeostasis and function by dynamically regulating gene expression.Accumulating evidence has revealed the role of aberrant gene expression in CVD caused by dysregulated RNA modification.In this review,we focus on nine common RNA modifications:N^(6)-methyladenosine(m^(6)A),N^(1)-methyladenosine(m^(1)A),5-methylcytosine(m^(5)C),N^(7)-methylguanosine(m^(7)G),N^(4)-acetylcytosine(ac^(4)C),pseudouridine(Ψ),uridylation,adenosine-to-inosine(A-to-I)RNA editing,and modifications of U34 on tRNA wobble.We summarize the key regulators of RNA modification and their effects on gene expression,such as RNA splicing,maturation,transport,stability,and translation.Then,based on the classification of CVD,the mechanisms by which the disease occurs and progresses through RNA modifications are discussed.Potential therapeutic strategies,such as gene therapy,are reviewed based on these mechanisms.Herein,some of the CVD(such as stroke and peripheral vascular disease)are not included due to the limited availability of literature.Finally,the prospective applications and challenges of RNA modification in CVD are discussed for the purpose of facilitating clinical translation.Moreover,we look forward to more studies exploring the mechanisms and roles of RNA modification in CVD in the future,as there are substantial uncultivated areas to be explored.

Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice

Primary ciliary dyskinesia(PCD)is a congenital,motile ciliopathy with pleiotropic symptoms.Although nearly 50 causative genes have been identified,they only account for approximately 70%of definitive PCD cases.Dynein axonemal heavy chain 10(DNAH10)encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella.Based on the common axoneme structure of motile cilia and sperm flagella,DNAH10 variants are likely to cause PCD.Using exome sequencing,we identified a novel DNAH10 homozygous variant(c.589C>T,p.R197W)in a patient with PCD from a consanguineous family.The patient manifested sinusitis,bronchiectasis,situs inversus,and asthenoteratozoospermia.Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia,and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella.Subsequently,animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD,including chronic respiratory infection,male infertility,and hydrocephalus.To the best of our knowledge,this study is the first to report DNAH10 deficiency related to PCD in human and mouse models,which suggests that DNAH10 recessive mutation is causative of PCD.

Mutant CARD10 in a family with progressive immunodeficiency and autoimmunity

Autoimmunity and immunodeficiency were previously considered to be mutually exclusive conditions.However,an increased understanding of the complex immune regulatory systems and signaling mechanisms,coupled with the application of genetic analysis,has demonstrated the complex relationships between the two kinds of diseases.1 In recent years,several mild forms of primary immunodeficiencies have been discovered,presenting with opportunistic infections overlapping autoimmunity and/or allergy late in life.

Haploinsufficiency of syncoilin leads to hypertrophic cardiomyopathy

Here we reported a SYNC nonsense variant in a Chinese family with hypertrophic cardiomyopathy(HCM)and firstly linked syncoilin(SYNC)to HCM.HCM is an inherited cardiovascular disease,affecting approximately 1:500 people,that is characterized by thickening of left ventricle(LV),especially the interventricular septum(IVS),and diastolic ventricular failure.1 To date,more than 15 genes of two groups underlying HCM have been identified.1 About 35%e60%HCM patients present autosomal dominant inheritance and carry a pathogenic variant in sarcomeric protein genes,such as b-myosin heavy chain(MYH7),myosin binding protein C(MYBPC3),and Troponin T(TNNT2).1 In addition,non-sarcomeric genetic causes of disease have also been observed in about 25%HCM patients,mainly related to metabolic storage diseases,mitochondrial cardiomyopathies,inborn errors of metabolism etc.