Overview

Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr11:121429346 C>T
dbSNP ID: rs148966249
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to TGG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 20

Findings

The SORL1 R904W variant was identified in a Colombian family with early onset Alzheimer’s disease, but the variant did not segregate with disease. The family included nine affected members in three generations. Pedigree analysis suggested an autosomal dominant pattern of inheritance. Since the family hails from the same region of Colombia as the well described kindred harboring the E280A (Paisa) mutation in PSEN1, the PSEN1 gene (exons 4 to 13, with flanking introns) was sequenced in the proband and an unaffected sibling. While the E280A mutation was absent, both individuals carried the PSEN1 14:73664853G>T (GRCh37, rs165932) variant in intron 8.

Whole-exome sequencing was then conducted on these two family members and an additional affected sibling. Nine variants in seven candidate genes were identified—selected based on criteria including presence in the AlzGene database, minor allele frequency of less than 5 percent in population databases, and in silico predictions of damage. The proband was found to be heterozygous for the c.C2710T, p.R904W variant in SORL1, as well as variants in CHAT (Choline O-acetyltransferase; c.G770A, p.R257Q), ABCA7 (ATP binding cassette subfamily A member; c.G2629A, p.A877T), LPA (Lipoprotein A; c.A5673G, p.I1891M), and APOE (Apolipoprotein E; c.T388C, p. C130R, the E4 allele). The other candidate variants identified in this family are p.R556P (c.G1667C) in MAPT (Microtubule-associated protein tau), p. L1768fs (c.5302delC) and p.G215S (c.G643A) in ABCA7, and p.R564H (c.G1691A) in MTHFD1L (Methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like). No mutations in the coding regions of APP, PSEN1 or PSEN2 were found. Finally, eight additional family members were genotyped for each of the candidate variants (in total, four affected and seven unaffected family members were genotyped).

The SORL1 R904W variant did not segregate with disease in this family. Among the five carriers of the variant, two were affected—the proband (age of onset 63 years) and his sister (age of onset 70 years). The three unaffected carriers are a sister of the proband and two of his daughters (cognitively healthy at ages 60, 38 and 42, respectively), with the latter two individuals several years younger than the earliest reported age of symptom onset in this family. Among the six non-carriers of the SORL1 variant, two were affected (both 60 years old at symptom onset) and four unaffected (ages 35, 54, 68, and unknown). The two affected non-carriers were a brother and cousin of the proband; both carried the MTHFD1L p.R564H variant. All genotyped family members were APOE E3/E4, except for one individual—cognitively healthy at age 60—who is E4/E4.

Neuropathology

The proband had neuropathologically confirmed Alzheimer’s disease—amyloid plaques (CERAD C, Thal phase 4) and neurofibrillary tangles (Braak stage 5)—as well as lung cancer that had metastasized to the brain. Cerebral amyloid angiopathy was present but scant (score 1, per Love et al., 2014).

Functional Consequences

Arginine-904 is found within the YWTD-repeated β-propeller domain (Andersen et al., 2023). Arginines are found at equivalent positions in five of the six blades of the YWTD-repeated β-propeller, where they are thought to interact with the tyrosines of the YWTD motifs to stabilize the domain. Based on domain mapping of disease mutations, Andersen and colleagues predicted that mutations of arginine-904 are highly likely to increase the risk of Alzheimer’s disease—variants in homologous positions in LRP5 are found in patients with osteoporosis-pseudoglioma syndrome and exudative vitreoretinopathy, in LRP4 in patients with congenital myasthenic syndrome, and a mutation in LRP6 segregated with disease in a family with metabolic syndrome.

The variant was predicted to be damaging by PolyPhen-2 and SIFT. Computational modeling showed that the arginine-to-tryptophan substitution at amino acid 904 should affect the hydrophobicity of the surrounding region, potentially leading to structural and functional changes in the protein (Tejada Moreno et al., 2022).

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References

Mutations Citations

1. PSEN1 E280A (Paisa)

Basic page Citations

1. AlzGene 3 Dec 2013

Paper Citations

1. Love S, Chalmers K, Ince P, Esiri M, Attems J, Jellinger K, Yamada M, McCarron M, Minett T, Matthews F, Greenberg S, Mann D, Kehoe PG. Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue. Am J Neurodegener Dis. 2014;3(1):19-32. Epub 2014 Mar 28 PubMed. Correction.
2. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.
3. Tejada Moreno JA, Villegas Lanau A, Madrigal Zapata L, Baena Pineda AY, Velez Hernandez J, Campo Nieto O, Soto Ospina A, Araque Marín P, Rishishwar L, Norris ET, Chande AT, Jordan IK, Bedoya Berrio G. Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer's disease in a multigenerational Colombian Family. PLoS One. 2022;17(7):e0269955. Epub 2022 Jul 29 PubMed.

Further Reading

No Available Further Reading