Last week we saw how the complex interplay of genetics and environment has impacted the inheritance of sickle-cell anemia. This week, I want to talk about a special subset of inherited diseases called sex-linked disorders. One of the most common sex-linked disorders is Duchenne muscular dystrophy (DMD), a debilitating muscular disorder linked to the X-chromosome. Sex-linked disorders, like DMD, come from genes in the sex chromosomes (X and Y in humans). Sex chromosomes are responsible for determining an individual’s biological sex, XX for female, XY for male (although there are other less common combinations that come from chromosomal aberrations—we’ll talk about those more in the future).
What makes sex-linked inheritance so unique, however, is that these genes exclusively appear on the X chromosome. Additionally, to make up for the different levels of gene expression, XX individuals turn off one of the X chromosomes in each of their cells. Because different cells choose to turn off different X chromosomes, certain traits can be expressed in a patchwork throughout the individual’s body. This is best seen in calico cats—female cats inherit two different sex-linked fur color genes, which are expressed in patches. DMD is an X-linked recessive gene. Recessive genes normally require two copies (one from each parent) to be expressed, but in XY individuals, only one copy of the aberrant gene is needed (from the mother) since the Y chromosome doesn’t carry the gene at all.
Humans have 22 pairs of autosomal chromosomes (non-sex chromosomes) and 1 pair of sex chromosomes for a total of 46. The autosomal chromosome pairs are identical in terms of what genes they contain, but they can have different variants of that gene (gene variants are typically called alleles). This means that every cell in the body contains two of each gene, except for the gametes (egg or sperm cells). Gametes only have one of each chromosome pair, and the alleles are distributed semi-randomly to each gamete. A baby inherits one copy of each gene from each of their parents to form their complete set of 46 chromosomes. In terms of the sex chromosomes, a baby inherits an X chromosome from their mother and either an X or a Y from their father, which determines their biological sex.
Most alleles are either dominant or recessive, which dictates how the gene is expressed. If an individual has one dominant allele and one recessive allele (they are heterozygous for that gene), then the dominant one usually controls expression. An example would be brown versus blue eye color—the brown eye allele is dominant so two parents with brown eyes are less likely to have a blue-eyed baby. Eye color is actually much more complex than this and linked with the genetics of hair and skin color (plus, this explanation leaves out the most important eye color, green). In this simplified view of inheritance, the only way for a recessive allele to be expressed is if both copies of the gene are recessive (two blue eye genes, one from each parent).
In individuals with two X chromosomes, X-linked alleles interact in pretty much the same way as autosomal alleles. The allele for Duchenne muscular dystrophy is recessive, so XX individuals need two copies of the allele from each of their parents to experience the disease. If only one of their X chromosomes has the DMD allele, then they are considered a carrier of the disease—they don’t experience any of the negative side effects, but they can pass the disease on to their children. On the other hand, XY individuals only need one copy of the DMD allele (from their carrier mother, since their father gave them the Y chromosome) to experience the disease.
The Duchenne muscular dystrophy allele is a mutated form of the dystrophin gene. Dystrophin is a protein found in muscle tissues, including the heart, that stabilizes muscle and facilitates chemical signaling between muscle cells. The mutated DMD gene encodes for a dystrophin protein that is not functional, causing muscle degeneration and heart problems. In heterozygous XX carriers, the normal dystrophin gene makes enough of the protein to maintain normal muscular function.
Approximately 1 in every 3500 male babies has Duchenne muscular dystrophy, which often causes symptoms before the age of six. DMD babies may not sit, stand, or walk as early as their healthy counterparts, and muscle weakness may affect their ability to get around. The muscles continue to decay over time until the individual is confined to a wheelchair (usually by the age of 12). Difficulty breathing and heart disorder continue to plague the DMD individual and cause early mortality (usually by their 30s).
Currently, the treatment for Duchenne muscular dystrophy is primarily focused on managing the symptoms, but scientists are constantly looking for better treatments that target the disorder at its source. Recently, researchers have been able to successfully use CRISPR-Cas9 to correct the mutated dystrophin gene in the muscle cells of DMD mice. The results of the experiment were promising and it’s possible that gene editing could permanently provide functional dystrophin for DMD individuals. Additionally, genetic screening and selective in vitro fertilization (IVF) can already be used to prevent DMD carrying mothers from passing the gene on to their children. Selective IVF involves screening potential embryos for the gene mutation before implanting them back into the mother. A mother who is a DMD carrier normally has a 50% chance of passing the mutation on to a child, but through selective IVF, it’s possible to single out viable embryos without the debilitating mutation.
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