Collection
Genetic Models of Rare Diseases
Genes and variants of interest in rare diseases often benefit from modelling in cellular assays or genetic models to aid in understanding molecular and cellular mechanisms of disfunction. Model organisms are useful for the discovery of new genetic diseases and key to understanding variant effects, and modelling a disease gene in a genetic model means that researchers can perform an in-depth exploration of gene or variant function. These studies can pinpoint disease mechanisms, reveal unanticipated gene functions, or elucidate specific existing pathways. Unravelling the mechanism(s) by which variants act can highlight potential therapeutic strategies to help patients.
The GSA Journals are pleased to publish a series highlighting ongoing advances in rare disease discovery and mechanisms by presenting key research findings and new discoveries.
Overseen by Series Editors Brenda Andrews (University of Toronto), Hugo Bellen (Baylor College of Medicine), Douglas Fowler (University of Washington School of Medicine), and Philip Hieter (University of British Columbia), this series launched in August 2023 with an accompanying editorial and a block of 9 research papers. Authors are invited to submit manuscripts to the series on an ongoing basis.
Rapid and low-cost sequencing, as well as computer analysis, have facilitated the diagnosis of many genetic diseases, resulting in a substantial rise in the number of disease-associated genes. However, genetic diagnosis of many disorders remains problematic due to the lack of interpretation for ...
Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain size, intellect, and life span whose etiology remains poorly understood. Here, Mannino et al. provide the neurodevelopmental transcriptional landscape of a Drosophila model of MCPH5 caused by mutations in abnormal spindle. They characterize asp expression across cell-types and developmental stages, solidifying its role as a neurogenesis-promoting factor, and identify new pathways important for Asp-dependent brain growth through gene expression profiling and mutational analysis.
Mutations in the chromosome cohesion apparatus lead to developmental disorders called cohesinopathies, which have been attributed to changes in transcription. Here, Chen et al. exploit sensitive assays in budding yeast to assess the impacts of disease-associated mutations in the highly conserved cohesin subunit SMC1 on chromosome segregation and cell cycle progression. Their data suggests that some of the phenotypes in Cornelia de Lange Syndrome—a cohesinopathy—might also be attributable to cell cycle defects due to compromised sister chromatid cohesion.
Spinocerebellar Ataxia Type 17 (SCA17) is the most recently identified member of the polyglutamine (polyQ) family of disorders, resulting from abnormal CAG/CAA expansion in the TATA box-binding protein (TBP), an initiation factor essential for of all eukaryotic transcription. A largely autosomal ...
Peterson et al. describe the first genetic mapping of the “golden” rhesus macaque phenotype, a naturally occurring pigmentation trait. Using independent analyses of macaques at two different US Primate Research Centers the authors were able to attribute the phenotype to 3 different variants in the TYRP1 and TYR genes. They highlight the use of the macaque Genotype and Phenotype (mGAP) Resource to identify the genetic basis for the trait and its applicability as a non-human primate genetic model for oculocutaneous albinism.
Philip Hieter and others
Genetics, Volume 224, Issue 4, August 2023, iyad121, https://doi.org/10.1093/genetics/iyad121
To highlight the development of new model systems, assays, and resources designed to illuminate rare disease gene function, the Genetics Society of America has launched a special collection of publications in the GSA journals GENETICS and G3: Genes|Genomes|Genetics.
Michael J Gruss and others
Genetics, iyad066, https://doi.org/10.1093/genetics/iyad066
TWIST1 is a basic helix-loop-helix (bHLH) transcription factor in humans that functions in mesoderm differentiation. TWIST1 primarily regulates genes as a transcriptional repressor often through TWIST-Box domain-mediated protein–protein interactions.
Sarah E Wetzel-Strong and others
Genetics, iyad077, https://doi.org/10.1093/genetics/iyad077
Sturge–Weber Syndrome (SWS) is a sporadic (non-inherited) syndrome characterized by capillary vascular malformations in the facial skin, leptomeninges, or the choroid. A hallmark feature is the mosaic nature of the phenotype.
Mary L Kaldunski and others
Genetics, iyad078, https://doi.org/10.1093/genetics/iyad078
Rare diseases individually affect relatively few people, but as a group they impact considerable numbers of people. The Rat Genome Database (https://rgd.mcw.edu) is a knowledgebase that offers resources for rare disease research.
Mary Bergwell and others
Genetics, iyad105, https://doi.org/10.1093/genetics/iyad105
The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear.
Rebecca A MacPherson and others
Genetics, iyad061, https://doi.org/10.1093/genetics/iyad061
Switch/sucrose nonfermentable (SWI/SNF)-related intellectual disability disorders (SSRIDDs) and Cornelia de Lange syndrome are rare syndromic neurodevelopmental disorders with overlapping clinical phenotypes.
Sharayu V Jangam and others
Genetics, iyad110, https://doi.org/10.1093/genetics/iyad110
EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease.
Xu Cao and others
G3 Genes|Genomes|Genetics, jkad007, https://doi.org/10.1093/g3journal/jkad007
Loss-of-function mutations of FIG4 are responsible for neurological disorders in human and mouse that result from reduced abundance of the signaling lipid PI(3,5)P2.
Maria C Sterrett
G3 Genes|Genomes|Genetics, jkad049, https://doi.org/10.1093/g3journal/jkad049
The RNA exosome is a conserved molecular machine that processes/degrades numerous coding and non-coding RNAs. The 10-subunit complex is composed of three S1/KH cap subunits (human EXOSC2/3/1; yeast Rrp4/40/Csl4), a lower ring of six PH-like subunits (human EXOSC4/7/8/9/5/6; yeast Rrp41/42/43/45/46/Mtr3), and a singular 3′-5′ exo/endonuclease DIS3/Rrp44.
Mark J Swanson and others
G3 Genes|Genomes|Genetics, jkad057, https://doi.org/10.1093/g3journal/jkad057
Alzheimer's disease (AD) is an age-related disorder that results in progressive cognitive impairment and memory loss. Deposition of amyloid β (Aβ) peptides in senile plaques is a hallmark of AD.
Natalie Hammond and others
Genetics, iyad129, https://doi.org/10.1093/genetics/iyad129
Niemann–Pick type C (NP-C) disease is a rare lysosomal storage disease caused by mutations in NPC1 (95% cases) or NPC2 (5% cases). These proteins function together in cholesterol egress from the lysosome, whereby upon mutation, cholesterol and other lipids accumulate causing major pathologies.
