Biology subjects

Greenberg, B.

Publications and source records attributed to Greenberg, B..

3 recordsLinked to original sources

bioRxiv2025

A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1) causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS)

Mutations in PIK3R1, a regulatory subunit of Class I PI3K, are implicated in immune disorders and neurological conditions. We identified a novel heterozygous pathogenic frameshift mutation (c.1710dup) in PIK3R1 in a patient with common variable immunodeficiency who developed slowly progressive Amyotrophic Lateral Sclerosis. Induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs) demonstrated that this mutation resulted in PIK3R1 haploinsufficiency, with downstream activation of AKT, disruption of neuronal electrical function and increased apoptosis in iPSC-derived motor neurons. Single-cell RNA sequencing (scRNA-seq) and pathway analysis of differentially expressed genes showed apoptosis pathways were upregulated in neuronal clusters from iMNs harboring the PIK3R1c.1710 dup mutation. Mutated iPSC-derived brain organoids were smaller than matched controls. scRNA-seq of brain organoids showed more active apoptosis in neuronal clusters of patient-derived brain organoids. These findings identify a critical and novel role for PIK3R1 haploinsufficiency in neuronal function and survival.

neuroscience↗

bioRxiv2022

Control of Craniofacial Development by the Collagen Receptor, Discoidin Domain Receptor 2

Development of the craniofacial skeleton requires interactions between progenitor cells and the collagen-rich extracellular matrix (ECM). The mediators of these interactions are not well-defined. Mutations in discoidin domain receptor 2 (DDR2), a non-integrin collagen receptor, are associated with craniofacial abnormalities, such as midface hypoplasia and open fontanels. However, the exact role of DDR2 in craniofacial morphogenesis is not known. As will be shown, Ddr2-deficient mice exhibit defects in craniofacial bones including impaired calvarial growth and frontal suture formation, cranial base hypoplasia due to aberrant chondrogenesis and delayed ossification at growth plate synchondroses. As established by localization and lineage tracing studies, Ddr2 is expressed in progenitor cell-enriched craniofacial regions including sutures and synchondrosis resting zone cartilage, overlapping with Gli1+ cells, and contributing to chondrogenic and osteogenic lineages during skull growth. Tissue-specific knockouts further established the requirement for Ddr2 in Gli1+ skeletal progenitors and chondrocytes and suggest important functions in chondrocyte proliferation and orientation as well as ECM organization. These studies establish a cellular basis for regulation of craniofacial morphogenesis by this understudied collagen receptor.

developmental biology↗

bioRxiv2018

The Healthy Pregnancy Research Program: Transforming Pregnancy Research Through a ResearchKit App

Although maternal morbidity and mortality in the U.S. is among the worst of developed countries, pregnant women have been under-represented in research studies, resulting in deficiencies in evidence-based guidance for treatment. There are over two billion smartphone users worldwide, enabling researchers to easily and cheaply conduct extremely large-scale research studies through smartphone apps, especially among pregnant women in whom app use is exceptionally high, predominantly as an information conduit. We developed the first pregnancy research app that is embedded within an existing, popular pregnancy app for self-management and education of expectant mothers. Through the large-scale and simplified collection of survey and sensor generated data via the app, we aim to improve our understanding of factors that promote a healthy pregnancy for both the mother and developing fetus. From the launch of this cohort study on March 16, 2017 through December 17, 2017, we have enrolled 2,058 pregnant women from all 50 states. Our study population is diverse geographically and demographically, and fairly representative of U.S. population averages. We have collected 14,045 individual surveys and 11,669 days of sleep, activity, blood pressure and heart rate measurements during this time. On average, women stayed engaged in the study for 59 days and 45 percent who reached their due date filled out the final outcome survey. During the first nine months, we demonstrated the potential for a smartphone-based research platform to capture an ever-expanding array of longitudinal, objective and subjective participant-generated data from a continuously growing and diverse population of pregnant women.\n\nFundingSupported in part by the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences grant UL1TR001114 and a grant from the Qualcomm Foundation.

epidemiology↗