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

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . SORL1 Variants in Familial Alzheimer's Disease. J Alzheimers Dis. 2018;61(4):1275-1281. PubMed.
  2. . 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

  1. . 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.

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.

AlzAntibodiesAlzBiomarkerAlzRiskBrain BanksGeneticsAlzGeneHEXMutationsProtocolsResearch ModelsTherapeutics