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EOFAD 101 : Mutations

Introduction

In this article, we answer many of the frequently asked questions about mutations* and how they relate to early onset familial Alzheimer’s disease (EOFAD).

If you haven’t already done so, we recommend checking out EOFAD 101: Genetics before reading with this article.

*Here at Youngtimers, we use the word “mutation” to describe a disease-causing change in a gene, however, some people also use the term “variant” to describe a genetic change. See below to learn more about why we chose “mutation.”

What mutations cause EOFAD?

Mutations in one of three genes: the amyloid precursor protein (APP) gene, the presenilin 1 (PSEN1 or PS1) gene, or the presenilin 2 (PSEN2 or PS2) gene result in early-onset familial Alzheimer’s disease (EOFAD). There are several different mutations in these three genes that result in disease and, depending on the mutation, can cause varying age of onsets, disease duration, and symptoms in affected individuals.

What are the most prevalent EOFAD mutations?

APP V717L (also known as the London mutation)
PSEN1 H163R
PSEN1 G206A (found in many families from Puerto Rico and the Dominican Republic)
PSEN1 E280A (also known as the Paisa mutation, found in a large family that lives in Antioquia, Colombia)
PSEN1 A431E (also known as the Jalisco mutation, found in many families with descendents from Jalisco, Mexico)
PSEN2 N141I (also known as the Volga German mutation)

How many EOFAD mutations are there?

Based on current scientific literature and databases, the total number of mutations that can cause EOFAD range from 230 – 463 mutations. These are all mutations in APP, PSEN1, and PSEN2: 176 - 326 PSEN1 mutations, 32 - 69 mutations in APP, and 14 - 68 PSEN2 mutations have been reported.

References: Ryman et al. 2014, Bekris et al. 2010, and AlzForum.

What do I need to know to understand my mutation?

The DNA code – the instruction manual for our bodies:

As we explain in EOFAD 101: Genetics, genes code (or provide the instruction manual) for certain things in our body, such as our eye color or blood type. However, in order to have a code, you need an alphabet or letters to write the instruction manual. This is where DNA comes in.

There are four units of DNA, called nucleotides: adenine (A), thymine (T), cytosine (C) and guanine (G). Specialized machinery in our body can read different combinations of these nucleotides and begin creating amino acids, the building blocks of the proteins in our bodies.

Turning the DNA code into protein:

Three nucleotides, also referred to as a codon, serve as the main code to generate one amino acid. Specific combinations of these nucleotides (A, T, C, G) will help tell specialized machinery to make a specific amino acid. There are about 20 different types of amino acids.

you can find a diagram of all amino acids and their abbreviations and structures here.

As a way of mapping where all the nucleotides in our DNA are located, the site of every three nucleotides (or codons) are numbered within a gene.

Let's use an example of an actual early-onset familial Alzheimer's disease gene:

In a normal PSEN1 gene, at site 280, the DNA code produces the amino acid Glutamic acid (also referred to as Glu or E). That amino acid, Glutamic acid, combines with other amino acids generated by the PSEN1 gene to make up the protein presenilin-1.

What does my specific mutation mean?

Let's use that same example of an actual early onset familial Alzheimer's disease mutation:

PSEN1 with mutation p.Glu280Ala, which also means E280A.

How do we determine what the E280A stands for?

In a normal PSEN1 gene, at site 280, the DNA code produces the amino acid Glutamic acid (also referred to as Glu or E). However, in a PSEN1 gene with a E280A mutation, the mutation changes the genetic code resulting in the production of the amino acid Alanine (also referred to as Ala or A). So E was exchanged for A at site 280. If the incorrect amino acid is produced this means the normal protein cannot be built, disrupting its normal function.

Where can I find information on my specific mutation?

We recommend looking at the scientific article by Ryman et al. 2014, specifically their Supplemental Table 1, which provides a list of many mutations with information such as year of onset, number of individuals with the mutation, and disease duration. If you have trouble accessing this information, please contact us and we can send you the information you need.

Another great resource is the Alzforum.org mutation database. Here, you can search your specific mutation and find out about previous scientific findings, including what families/countries it has been found in.

Why do we use the term mutation? How is a variant and a mutation different?

It might seem strange to some that we feel the need to explain why we use the term mutation since it is such a common word, but there is a lot of discussion in the field of genetics surrounding whether or not to retire the term.

Here’s why: “mutation” has been used by geneticists since the inception of the study of genetics to describe variation. However, as science and research evolves, so too does language. Many researchers and medical professionals, such as genetic counselors, feel that the term “mutation” doesn’t accurately reflect what is known about genetics today. What we know is that some genetic mutations have no negative impact on a person’s health at all. A change in a gene from what is “normal” can be as benign as the reason behind why some people have blue eyes and some people have brown eyes. Some genetic mutations are neutral and are the reason why there’s normal variation between each and every individual.

To reflect the possible neutrality of a genetic mutation, the American College of Medical Genetics and Genomics (ACMG) issued guidelines in 2015 that recommend the usage of the term “variant” in place of “mutation.” In their guidelines, they created a classification system to help medical professionals interpret the impact of a variant. Variants are classified as:

Benign (no impact on health)
Likely Benign (likely no impact on health, but not enough evidence to say with certainty)
Unknown Significance (not enough evidence to classify a variant as either benign or pathogenic)
Likely Pathogenic (likely disease-causing, but not enough evidence to say with certainty)
Pathogenic (disease-causing)

As an organization that feels strongly about providing accurate scientific information, we are happy that this new terminology reflects science accurately and that it’s becoming more commonly used. However, we know that many in our community hold the term “mutation” closely to their heart. That’s because our EOFAD community has a history of embracing the term “mutation,” with many calling themselves “mutants” and the “X-Men.”

Our community finds great strength in our greatest weakness -- we are a community of superheroes who have the ability to find a cure for Alzheimer’s disease. For this reason, we choose to use the term mutation instead of variant. Just know that when you see “mutation” used by us, we are referring to “likely pathogenic” variants and “pathogenic” variants.