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Science Papers on Variants Linked to Primary Lymphedema, Parkinson's Disease Treatment Targets

An analysis of multiple patients with primary lymphedema — a rare condition of the lymphatic vascular system with autosomal dominant inheritance — reveals new disease-causing mutations. The 28 genes currently known to cause primary lymphedema only account for less than 30 percent of all cases. In a study appearing in Science Translational Medicine, a team led by scientists from Biomedicum Helsinki performed a genetic screen of 543 people with primary lymphedema with a focus on the genes that encode ANGPT proteins, which are involved in proper blood and lymphatic vessel formation and remodeling during embryonic development, as well as mature vasculature homeostasis. They found that seven of the patients lacked mutations in the 28 known disease-associated genes but had either a heterozygous de novo ANGPT2 whole-gene deletion or one of four heterozygous ANGPT2 missense mutations. Functional analyses revealed that three of the missense mutations resulted in decreased ANGPT2 secretion, while the fourth interfered with ANGPT2's ability to bind to integrin. "Our data underscore loss of ANGPT2 function as a mechanism leading to primary lymphedema," they write.

By studying the effects of a mutation in the Parkinson's disease-linked gene PARK7 in patient-derived cellular models, researchers from the University of Luxembourg and their collaborators have uncovered new treatment targets for the disease. Mutations in PARK7 are known to cause a rare form of early-onset Parkinson's disease (PD), but the effects of these mutations at the cellular level are unknown. As reported in Science Translational Medicine this week, the scientists used a patient-based in vitro model of PARK7-linked PD to identify an exonic splicing mutation in the gene that reduces production of the DJ-1 protein, leading to mitochondrial dysfunction. Treatment with two small-molecule compounds — rectifier of aberrant splicing, or RECTAS, and phenylbutyric acid — could rescue the aberrant splicing to restore DJ-1 production and mitochondrial function in patient-derived fibroblasts, as well as dopaminergic neuronal cell loss in mutant midbrain organoids. "Our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD," the researchers conclude.

The Scan

Machine Learning Helps ID Molecular Mechanisms of Pancreatic Islet Beta Cell Subtypes in Type 2 Diabetes

The approach helps overcome limitations of previous studies that had investigated the molecular mechanisms of pancreatic islet beta cells, the authors write in their Nature Genetics paper.

Culture-Based Methods, Shotgun Sequencing Reveal Transmission of Bifidobacterium Strains From Mothers to Infants

In a Nature Communications study, culture-based approaches along with shotgun sequencing give a better picture of the microbial strains transmitted from mothers to infants.

Microbial Communities Can Help Trees Adapt to Changing Climates

Tree seedlings that were inoculated with microbes from dry, warm, or cold sites could better survive drought, heat, and cold stress, according to a study in Science.

A Combination of Genetics and Environment Causes Cleft Lip

In a study published in Nature Communications, researchers investigate what combination of genetic and environmental factors come into play to cause cleft lip/palate.