Mutations
SORL1 c.4519+5G>A
Overview
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121595777 G>A
Position: (GRCh37/hg19):Chr11:121466486 G>A
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA
Change: Substitution
Reference
Isoform: SORL1 Isoform 1 (2214 aa)
Genomic
Region: Intron 32
Findings
This variant disrupts the 5' splice donor site in intron 32 and is predicted to cause exon skipping. It was found, in heterozygosity, in a Spanish individual with neuropathologically confirmed early onset Alzheimer’s disease (Gómez-Tortosa et al., 2018; Alvarez-Mora et al., 2022).
The carrier’s symptoms became apparent at age 53 (Gómez-Tortosa et al., 2018; Alvarez-Mora et al., 2022). In addition to episodic memory impairment and problems with word finding, he also experienced apathy, irritability, impulsivity, and developed a binge eating disorder. This constellation of symptoms led to a clinical diagnosis of possible AD or behavioral variant frontotemporal dementia. Within six years, the patient required complete assistance with activities of daily living, and he died 12 years after the onset of symptoms (Alvarez-Mora et al., 2022).
At the time of symptom onset, MRI of the brain appeared normal, but SPECT showed frontal hypoperfusion. Three years later, MRI showed mild-to-moderate brain atrophy (Alvarez-Mora et al., 2022).
The proband’s mother had been diagnosed with early onset Alzheimer’s disease. While two brothers were said to be cognitively normal, their ages were not reported. Genotype information was not available from family members (Alvarez-Mora et al., 2022).
The variant was absent from a control population of 200 elderly Spanish subjects (Gómez-Tortosa et al., 2018).
Neuropathology
Postmortem examination showed Alzheimer’s neuropathology—amyloid plaques (Thal stage 4, CERAD score 2) and neurofibrillary tangles (Braak stage V). Type 2 cerebral amyloid angiopathy—characterized by amyloid deposits in leptomeningeal and cortical vessels, other than capillaries—was also present. TDP-43 cytoplasmic inclusions were seen in neurons in the hippocampus and amygdala. Alpha-synuclein deposits were not observed (Alvarez-Mora et al., 2022).
Functional Consequences
SORL1 immunoreactivity in the hippocampus was qualitatively similar in the proband, cases of sporadic late-onset AD who did not carry this SORL1 variant, and a cognitively normal control: Fine granular staining was present in the cytoplasm of pyramidal neurons (Alvarez-Mora et al., 2022).
As mentioned above, this variant is predicted to cause exon skipping.
Last Updated: 18 Jul 2024
References
Paper Citations
- Gómez-Tortosa E, Ruggiero M, Sainz MJ, Villarejo-Galende A, Prieto-Jurczynska C, Venegas Pérez B, Ordás C, Agüero P, Guerrero-López R, Pérez-Pérez J. SORL1 Variants in Familial Alzheimer's Disease. J Alzheimers Dis. 2018;61(4):1275-1281. PubMed.
- Alvarez-Mora MI, Blanco-Palmero VA, Quesada-Espinosa JF, Arteche-Lopez AR, Llamas-Velasco S, Palma Milla C, Lezana Rosales JM, Gomez-Manjon I, Hernandez-Lain A, Jimenez Almonacid J, Gil-Fournier B, Ramiro-León S, González-Sánchez M, Herrero-San Martín AO, Pérez-Martínez DA, Gómez-Tortosa E, Carro E, Bartolomé F, Gomez-Rodriguez MJ, Sanchez-Calvin MT, Villarejo-Galende A, Moreno-Garcia M. Heterozygous and Homozygous Variants in SORL1 Gene in Alzheimer's Disease Patients: Clinical, Neuroimaging and Neuropathological Findings. Int J Mol Sci. 2022 Apr 11;23(8) PubMed.
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Alvarez-Mora MI, Blanco-Palmero VA, Quesada-Espinosa JF, Arteche-Lopez AR, Llamas-Velasco S, Palma Milla C, Lezana Rosales JM, Gomez-Manjon I, Hernandez-Lain A, Jimenez Almonacid J, Gil-Fournier B, Ramiro-León S, González-Sánchez M, Herrero-San Martín AO, Pérez-Martínez DA, Gómez-Tortosa E, Carro E, Bartolomé F, Gomez-Rodriguez MJ, Sanchez-Calvin MT, Villarejo-Galende A, Moreno-Garcia M. Heterozygous and Homozygous Variants in SORL1 Gene in Alzheimer's Disease Patients: Clinical, Neuroimaging and Neuropathological Findings. Int J Mol Sci. 2022 Apr 11;23(8) PubMed.
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