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This Week in Cell: Mar 7, 2018

Investigators at the Hospital for Sick Children, University of Toronto, University of Utah, and elsewhere explore mechanisms for medulloblastoma metastases to leptomeningeal tissue surrounding the brain and spinal cord. The team did whole-genome sequencing on primary medulloblastoma samples, peripheral blood samples, and matched leptomeningeal metastases from three individuals with the disease, a childhood cancer that begins in the brain's developing cerebellum. Along with insights into primary tumor clones contributing to metastases, the sequence data and subsequent experiments provided a look at metastases medulloblasoma movement to the leptomeningeal space via the blood, suggesting cerebrospinal fluid is not the only route for the tumor's spread. "Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma," the authors say.

Using a combination of genome and transcriptome sequencing, a Massachusetts General Hospital-led team trace a form of the neurodegenerative disease X-linked Dystonia-Parkinsonism (XDP) to TAF1, a gene that codes for a component of a transcription factor complex regulating RNA polymerase II transcription. The researchers began by doing de novo genome sequencing and assembling, long insert jumping library whole-genome sequencing, and long read and targeted sequencing on samples from nine individuals, before applying "capture for dense tiling and deep sequencing," or CapSeq to 403 men with XDP, nearly two dozen unaffected heterozygous female carriers, and more than 350 unaffected controls. From these and other data, they narrowed in on a SINE-VNTR-Alu retrotransposition insertion in TAF1 that altered the gene's splicing and dialed down its expression.

A Baylor College of Medicine-led team takes a look at the consequences of mutations in PUM1, a gene encoding an RNA-binding protein that represses Ataxin1. Following from prior analyses pointing to neurodegeneration in mice with PUM1 haploinsufficiency and enhanced Ataxin1 activity, the researchers rummaged through public and neurodevelopmental patient array databases, looking for individuals with copy number shifts in PUM1. Their search led to nine heterozygous PUM1 deletions in patients that were not found in unaffected controls, while additional searches unearthed individuals with missense mutations in the gene. From a series of follow-up analyses, the authors conclude that PUM1 haploinsufficiency leads to an early-onset condition marked by ataxia, seizures, and developmental delays, while milder dips in PUM1 activity were linked to forms of ataxia that manifest in adulthood.