TY - JOUR
T1 - Co-occurring pathogenic variants in 6q27 associated with dementia spectrum disorders in a Peruvian family
AU - Alvarez, Karla Lucia F.
AU - Aguilar-Pineda, Jorge Alberto
AU - Ortiz-Manrique, Michelle M.
AU - Paredes-Calderon, Marluve F.
AU - Cardenas-Quispe, Bryan C.
AU - Vera-Lopez, Karin Jannet
AU - Goyzueta-Mamani, Luis D.
AU - Chavez-Fumagalli, Miguel Angel
AU - Davila-Del-Carpio, Gonzalo
AU - Peralta-Mestas, Antero
AU - Musolino, Patricia L.
AU - Lino Cardenas, Christian Lacks
N1 - Publisher Copyright:
Copyright © 2023 Alvarez, Aguilar-Pineda, Ortiz-Manrique, Paredes-Calderon, Cardenas-Quispe, Vera-Lopez, Goyzueta-Mamani, Chavez-Fumagalli, Davila-Del-Carpio, Peralta-Mestas, Musolino and Lino Cardenas.
PY - 2023/2/16
Y1 - 2023/2/16
N2 - Evidence suggests that there may be racial differences in risk factors associated with the development of Alzheimer’s disease and related dementia (ADRD). We used whole-genome sequencing analysis and identified a novel combination of three pathogenic variants in the heterozygous state (UNC93A: rs7739897 and WDR27: rs61740334; rs3800544) in a Peruvian family with a strong clinical history of ADRD. Notably, the combination of these variants was present in two generations of affected individuals but absent in healthy members of the family. In silico and in vitro studies have provided insights into the pathogenicity of these variants. These studies predict that the loss of function of the mutant UNC93A and WDR27 proteins induced dramatic changes in the global transcriptomic signature of brain cells, including neurons, astrocytes, and especially pericytes and vascular smooth muscle cells, indicating that the combination of these three variants may affect the neurovascular unit. In addition, known key molecular pathways associated with dementia spectrum disorders were enriched in brain cells with low levels of UNC93A and WDR27. Our findings have thus identified a genetic risk factor for familial dementia in a Peruvian family with an Amerindian ancestral background.
AB - Evidence suggests that there may be racial differences in risk factors associated with the development of Alzheimer’s disease and related dementia (ADRD). We used whole-genome sequencing analysis and identified a novel combination of three pathogenic variants in the heterozygous state (UNC93A: rs7739897 and WDR27: rs61740334; rs3800544) in a Peruvian family with a strong clinical history of ADRD. Notably, the combination of these variants was present in two generations of affected individuals but absent in healthy members of the family. In silico and in vitro studies have provided insights into the pathogenicity of these variants. These studies predict that the loss of function of the mutant UNC93A and WDR27 proteins induced dramatic changes in the global transcriptomic signature of brain cells, including neurons, astrocytes, and especially pericytes and vascular smooth muscle cells, indicating that the combination of these three variants may affect the neurovascular unit. In addition, known key molecular pathways associated with dementia spectrum disorders were enriched in brain cells with low levels of UNC93A and WDR27. Our findings have thus identified a genetic risk factor for familial dementia in a Peruvian family with an Amerindian ancestral background.
KW - Alzheimer’s disease
KW - Amerindian ancestral background
KW - family-specific genetic factor
KW - unbiased gene discovery
KW - whole genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85149908693&partnerID=8YFLogxK
U2 - 10.3389/fnmol.2023.1104585
DO - 10.3389/fnmol.2023.1104585
M3 - Article
AN - SCOPUS:85149908693
SN - 1662-5099
VL - 16
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
M1 - 1104585
ER -