Bob’s mother, Frances Smith Russell, had struggled with her
own hearing problems for most of her life and as she aged the problems grew
worse. Each of Bob’s three siblings had hearing impairment of various degrees,
and so did several of their cousins, uncles, and grandfather. The family
realized there was a genetic problem affecting a wide range of Smith relatives.
With the success of the Human Genome Project in 2003 when DNA
sequencing was declared successfully complete, scientists began to study the origins
of genetic medical problems in families, starting with those that are most
devastating. And soon after that, Bob’s sister Mary voiced her hope that
someday, hopefully in her lifetime, someone would study the genetic hearing
impairment of the Smith family. She thought perhaps a graduate student would be
interested in making the study the subject of his or her thesis.
In the summer of 2016 researchers at the University
of Iowa agreed to include our
extended Smith family in an ongoing study they are conducting to identify the
specific genes that are responsible for genetic hearing loss, and map the exact
location on the genes where the mutations occur, since gene mutations are the cause
of genetic hearing loss. Mary had named this family malady “The Smith Family
Curse” and corresponded with many of her relatives to determine who were
affected and to encourage their participation in the study. She also compiled
complex family trees and gathered audiograms from afflicted relatives.
In November of 2016 the U of I sent saliva DNA
test kits to key members of the family, those whose audiograms showed similar
patterns of limited range, approximately seven of the twenty-five interested in
participating. After months of waiting we received an answer to our question in
August 2017. The mutant gene causing the Smith Family Curse is WFS1, Allele1:
chr4:6304014G>A; NM_001145853:c.2492G>A, p.Gly831Asp, Allele 2: normal
allele. This was offered as further clarification:
“Variants in WFS1 are
associated with low frequency autosomal dominant non-syndromic hearing loss at
the DFNA6/14/36 locus.”
I don’t pretend to understand this well. But I have googled
this subject and these finding and offer this amateur’s take on the findings. From
this website, https://ghr.nlm.nih.gov/gene/WFS1, I learned: "The WFS1 gene provides
instructions for producing a protein called wolframin that is thought to
regulate the amount of calcium in cells. A proper calcium balance is important
for many different cellular functions, including cell-to-cell communication,
the tensing (contraction) of muscles, and protein processing. The wolframin
protein is found in many different tissues, such as the pancreas, brain, heart,
bones, muscles, lungs, liver, and kidneys.
"Within cells, wolframin is located in the membrane of a
structure called the endoplasmic reticulum. Among its many activities, the
endoplasmic reticulum folds and modifies newly formed proteins so they have the
correct 3-dimensional shape to function properly. The endoplasmic reticulum
also helps transport proteins and other molecules to specific sites within the
cell or to the cell surface. Wolframin is thought to play a role in
protein folding and aid in the maintenance of endoplasmic reticulum function by
regulating calcium levels. In the pancreas, wolframin may help fold a
protein precursor of insulin (called proinsulin) into the mature hormone that
controls blood glucose levels. In the inner ear, wolframin may help
maintain the proper levels of calcium ions or other charged particles that are
essential for hearing." (I underlined those words “is thought” and “may” to
emphasize that researchers are still studying this protein and aren’t certain
of it’s functions.)
I also learned from reading various research papers found
online that because wolframin protein is not well understood in just how it
regulates calcium, among other things, the new gene editing technology, CRISPR,
is not being used at this time to edit this gene, at least not at the University
of Iowa. Until scientists really
understand all that wolframin does and how it does it, editing WFS1 to remove the mutation is risky. At
least, that is my understanding.
Apparently there are families in Japan,
the United States,
The Netherlands, and Spain
who, without being related to one another, show the same mutation of gene WFS1,
leading researches to surmise that there are locations on this gene that are
particularly susceptible to mutating. Fortunately for our family we did not
inherit the mutation of WFS1 that
causes Wolfram Syndrome. You can read about that on this website: https://en.wikipedia.org/wiki/Wolfram_syndrome.
Also, that site has a good explanation of our Smith Family Curse, and I quote:
“More than 30 WFS1 mutations have
been identified in individuals with a form of nonsyndromic deafness (hearing
loss without related signs and symptoms affecting other parts of the body)
called DFNA6. Individuals with DFNA6 deafness cannot hear low tones
(low-frequency sounds), such as a tuba or the "m" in moon. DFNA6
hearing loss is unlike most forms of nonsyndromic deafness that affect high
tones (high-frequency sounds), such as birds chirping, or all frequencies of
sound. Most WFS1 mutations replace one of the protein building blocks (amino
acids) used to make wolframin with an incorrect amino acid. One mutation
deletes an amino acid from wolframin. WFS1 mutations probably alter the
3-dimensional shape of wolframin, which could affect its function. Because the
function of wolframin is unknown, however, it is unclear how WFS1 mutations
cause hearing loss. Some researchers suggest that altered wolframin disturbs
the balance of charged particles in the inner ear, which interferes with the
hearing process.”
In conclusion, we
now know the cause of our family’s hereditary hearing loss, a gene mutation of WFS1. We know that this mutation is rare
but widely dispersed across the globe. Some researchers believe it is more
common than we know because loss of the lower ranges of hearing don’t keep
people from understanding human voices like loss in the higher ranges.
Consequently, many people with low frequency loss probably don’t look for
genetic testing. And we know, too, that until wolframin protein is better
understood we will not be candidates for gene editing.
I would like to thank everybody in our big, wonderful Smith family who participated in this study, including those who did not receive a saliva test from the University of Iowa. I was told that any family member can still participate (there is no deadline) but that the researchers require a blood sample now instead of a saliva sample. As quickly as DNA technology is changing and expanding I really expect to learn that gene editing to repair our family's gene mutation will become available someday soon.
