Monday, August 28, 2017

Smith Family Curse Mystery Solved

Since the time he was a young man Robert Doyle Russell knew that he had a hearing problem. It didn’t prevent him from joining the Navy in 1962 where he passed the most rigorous training the Navy had and still has, Basic Underwater Demolition / SEAL training, or BUD/S. His particular loss was mostly in the lower range… thunder, deep male voices, car mufflers. He learned to compensate for his hearing loss by reading lips and limiting his social interactions to one on one conversations but by 1966 when his Naval service was complete he knew he needed hearing aids.

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,,  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: 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.