Issues

Summary: This Editorial introduces DMM's new Special Issue on ‘Translating Multiscale Research in Rare Disease’. The Guest Editors reflect on how articles in the issue advance the rare disease research field.

Summary: Founder mutations account for increased prevalence of certain rare diseases within isolated groups in different populations. Here, we discuss the various implications of studying founder mutations in the Arab World.

Summary: TANGO2 deficiency disease, a rare condition featuring neurodegeneration and life-threatening metabolic crises, has a signature of lipid imbalance that can be compensated by supplementation of the CoA- and lipid-precursor vitamin B5.

Summary: Here, we summarise the issues surrounding access to gene therapy for rare diseases and explore potential solutions, and how they can be applied to improve access to these life-changing therapies.

Summary: The lack of diverse high-throughput functional assays for deep mutational scanning impedes genetic variant interpretation in rare disease research. This article reviews applicable assays across various molecular mechanisms.

Summary: Fusion-driven pediatric soft tissue sarcomas are aggressive and lack targeted therapies. Transgenic fusion-driven animal tumor models are a platform to understand tumorigenic mechanisms and translate findings into therapeutic strategies.

Summary: The mechanistic examination of the human condition combined with in vitro and in vivo modeling studies demonstrate how RAS pathway dysregulation in RASopathies affects mammalian skeletal muscle development.

Summary: Gain-of-function studies on human FZD2 missense variants associated with Robinow syndrome lead to increased facial width, altered WNT signaling and inhibition of beak skeletogenesis in chicken embryos.

Summary: Pathogenic variants in ATP1A3 cause alternating hemiplegia of childhood and related disorders. ATP1A3 supports the expression of heat shock proteins, thereby protecting cells from mitochondrial instability under heat stress.

Summary: MEK1-induced ERK1/2 hyperactivation in developing cortical excitatory neurons is sufficient to decrease long-range axonal outgrowth in mice, which coincides with reduced ARC levels and deficits in skilled motor learning by adulthood.

Summary: Alms1 knockout mice, although modelling many aspects of Alström syndrome, only weakly recapitulate the severe biphasic cardiomyopathy seen in humans. Adult female mice at 23 weeks show early systolic and diastolic dysfunction.

Summary: CDK13 plays a role in the regulation of facial morphogenesis as well as the growth of cranial peripheral nerves.

Summary: The characterization of a mouse model of a homozygous dystroglycan mutation causing muscle-eye-brain disease reveals defective embryonic development, myopathy and a disrupted gliovascular unit, offering novel insights into dystroglycanopathy pathogenesis.

Summary: Using a genetic mouse model of ataxia, we provide insights into the role of the cerebellum in sleep regulation, highlighting its importance as an origin for sleep disruptions in motor disorders.

Summary: Systemic treatment of female Rett syndrome mice with the brain-penetrant TrkB ligand LM22A-4 restores dendritic spine volume and aggressive behaviors to wild-type levels.

Summary: Fbrsl1 loss of function causes defects in Xenopus heart development. These defects can be rescued with a human FBRSL1 isoform, but not with variants identified in patients with heart defects.

Summary: Characterization of a mouse model of Snyder–Robinson syndrome reveals impaired neurological functions and mitochondrial respirations and provides a set of outcome measures to evaluate future therapeutic interventions.

Summary: Biochemical studies and in silico protein stability analyses reveal molecular mechanisms underlying the neurodevelopmental disorder CAMRQ4 associated with missense mutations in ATP8A2 and genetic diseases linked to other P4-ATPase lipid flippases.

Summary: In Caenorhabditis elegans, the endoplasmic reticulum protein LMBR-1 serves as a genetic suppressor of the specific seipin mutation associated with congenital generalized lipodystrophy.

Summary: Smad4, a commonly mutated gene in cholangiocarcinoma, restricts the cholangiocyte proliferative response to liver injury and oncogenic transformation via known/novel transcriptomic changes and genomic methylation patterns.

Summary: A mouse model carrying the pathogenic E122K mutation in Eef1a2 exhibits electrographic seizures and early motor abnormalities. Comparative phenotyping reveals a toxic gain-of-function or possible dominant-negative effect.

Editor's choice: Applying physiological mechanical stress to a human induced pluripotent stem cell model of Duchenne muscular dystrophy-related cardiomyopathy produces a biomarker signature similar to that seen in patients.

Summary: The use of standardised vocabularies of phenotypic abnormalities and algorithms for cross-species comparisons facilitates the automated and unbiased identification of mouse models of disease.