(PDF) Evaluation of Abnormal Bleeding in Children

Missing Y Chromosome In Mouse Blood Causes Heart Dysfunction

When Nettie Steven discovered the Y chromosome in 1905 while studying the mealworm Tenebrio molitor, she identified it as a sex-determining chromosome. As it turns out, the chromosome also has important functions beyond determining sex. According to a study published July 14 in Science, a lack of the Y chromosome in bone marrow cells causes heart failure.

The work was led by Lars Forsberg, a geneticist at Uppsala University in Sweden, and Kenneth Walsh of the University of Virginia. Their team zeroed in on mosaic loss of Y chromosome (mLOY), a condition where some of a male's somatic cells, particularly white blood cells, lose the Y chromosome. This condition, which is heavily associated with tobacco smoking, affects more than 40 percent of 70-year-old men in the UK Biobank cohort and is associated with a long list of illnesses, including Alzheimer's disease.

See "Vanishing Y Chromosomes"

In a previous study, Forsberg and his colleagues had found that the loss of the Y chromosome in men's blood cells increases their chances of developing cancer and of dying from any cause, and in the new work, he and Walsh went on to explore how this loss affects the heart. Prior to the new report, a study had already established an association between the loss of the Y chromosome and cardiovascular diseases; the authors say they wanted to go a step further and find out whether the relationship is causal. The team knocked out the chromosome in mice's bone marrow cells by deleting its centromere with CRISPR, mirroring the degeneration of the Y chromosome in male humans. The modification successfully induced blood chimerism—a condition where an individual has two sets of genetically different cells, in this case one with and one without the Y chromosome—in 81 percent of the mice. The researchers report that this scenario is consistent with the level of mosaic loss of Y chromosome (mLOY) in men that has been linked with Alzheimer's disease. In the study, the team observed that these mice had a shorter lifespan than unmodified controls.

When the researchers looked at the hearts of mLOY mice using ultrasound, they noticed the development of cardiomyopathy—a chronic disease of the heart muscle—that worsened with age. Further analysis showed an increase in the quantity of fibroblasts (a cell that donates materials for wound healing) and more scar tissue—known as fibrosis—in the heart. The researchers suggest in their paper that rapid fibrosis could serve as a marker for heart dysfunctions caused by mLOY.

Only 40 percent of the mLOY mice survived to 19 months of age, compared to more than 50 percent of the controls. Overall, says Forsberg, the study demonstrates "that this is more than an association. There's a causal effect from the loss of Y on the risk for cardiovascular disease."

To see how their findings might apply to humans, the team analyzed survival data of more than 200,000 men in the UK Biobank. They found that during an average follow-up time of 11.5 years, men with loss of Y chromosome in more than 40 percent of their white blood cells showed a 31 percent increased risk of cardiovascular disorders like hypertensive heart disease compared with men without mLOY.

Joseph Hill, a cardiologist at UT Southwestern Medical Center who was not involved in the study, says the research team made an "intriguing analysis" that provides evidence of a mechanistic link among loss of the Y chromosome, aging, and heart disease.

Hill notes that fibrosis is a complicated condition. For instance, it is a welcome development during a heart attack, as it promotes healing, but poses a threat when it emerges from high blood pressure. "Fibrosis is multifaceted. It [can] cut both ways: There are situations in which you would not want to target fibrosis and there are others in which you would want to target fibrosis therapeutically. The authors are suggesting that this may be one particular example" where it would be beneficial to target fibrosis therapeutically, Hill explains.

"It's certainly interesting and it fits well within the construct that fibrosis is driven by inflammation," says Don Rockey of the Medical University of South Carolina who studies fibrosis but did not participate in the study. He says he'd be interested in knowing whether this phenomenon occurs in other organs like the liver or kidney. However, he adds that it's unclear how the loss of the Y chromosome leads to inflammation in the heart.

Forsberg and his team also explored how the damage caused by a missing Y chromosome might be reversed. They treated the mLOY mice with an antibody targeting a protein called TGFβ1, which contributes to the spread of fibroblasts in the heart. The rate at which the fibroblasts proliferated in the mLOY mice's hearts fell, thus reversing the heart dysfunction. "The immune cells with loss of Y in the heart . . . Stimulate fibroblasts with this TGFβ1, thereby increasing fibrosis. What we saw in the mouse was that if we blocked the signaling pathway, the fibrosis disappeared," Forsberg says. "This [of] course has to be studied carefully, but it works in mice, so it might work in humans as well."

Rep. Nancy Mace Is Wrong. Not All People Are Born With Either XX Or XY Chromosomes.

We often hear the expression that there are two kinds of people in this world.

But that doesn't always apply when it comes to categorizing people by their sex chromosomes.

"You either have XX or XY chromosomes," Rep. Nancy Mace, R-S.C., wrote Feb. 20 on X. "Those are the options."

Most commonly, a person is born with two X chromosomes (female) or an X and a Y (male). But this is not always the case. 

Mace's claim ignores the existence of several medical conditions, some first observed by scientists as far back as the 1930s. Genetic testing in the 1950s enabled scientists to link these conditions to various chromosomal abnormalities in which people's sex chromosomes are neither XX nor XY.

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Mace's office did not respond to a request for comment before publication. After publication, her office wrote in a Feb. 21 email, "Barring chromosomal abnormalities, a person with a typical number of chromosomes — known as a euploid — has either XX or XY which determines biological sex."

About 1.7% of the worldwide population has intersex conditions or differences in sex development — cases in which someone's anatomy does not fit into male or female — according to a commonly cited review of medical literature published in 2000 by Brown University biologist Anne Fausto-Sterling. 

The conditions include: 

Klinefelter Syndrome (XXY): People with this condition, first identified in 1942, have an extra X chromosome. People with this syndrome are typically assigned male at birth; the condition can result in infertility, low testosterone and undescended testicles. It occurs in about 1 in 600 males. 

Turner Syndrome (missing or partial X): First identified in 1938, this syndrome occurs when a female is missing part of the X chromosome pair. This can cause short stature, delayed puberty, low sex hormones and possible infertility. 

Triple X Syndrome (XXX): The symptoms of this syndrome, also called trisomy X, can vary from mild — tall height — to more severe, including developmental delays. The condition, present in about 1 in 1,000 females, was first identified in 1959. 

Jacob's Syndrome (XYY): A relatively rare condition with mild symptoms, males with this syndrome are born with an extra Y chromosome. It occurs in about 1 in 1000 males and was identified in the 1960s. 

According to a factsheet released by the American Society for Reproductive Medicine, chromosomal variations "occur in an estimated 1 in 1,500 to 1 in 2,000 live births, which amounts to approximately 200,000 to 330,000 Americans based on the current population."

There are also intersex conditions that do not involve chromosomes because a person's "sex," according to scientists, is not easily measured by one factor. Chromosomes, gonads, hormones and genitalia can all contribute to a person's sex categorization.

People born with de la Chapelle syndrome have XX chromosomes but can develop a penis, because a gene typically found on the Y chromosome gets moved to a new position on the X chromosome.

People with androgen insensitivity syndrome have male chromosomes, but don't respond to their body's naturally produced male hormones, ranging from mild to complete insensitivity. In cases of complete insensitivity, genetically male fetuses (XY), with internal testes and normal testosterone production could develop vaginas and be assigned female at birth. Partial and mild insensitivity can result in more ambiguous sex characteristics. 

Other conditions also result in ambiguous genitalia that do not fall neatly into a male or female sex category.

"A lot of other variations might be noticeable at birth if they cause other types of genital differences," Sylvan Fraser Anthony, legal and policy director at Interact, a nonprofit advocating for intersex youth, told PolitiFact. "Others will be discovered, you know, not until later."

Our ruling

Mace wrote on X, "You either have XX or XY chromosomes. Those are the options."

Although most people are born with either XX or XY chromosomes, science dating back decades shows some people are born with other chromosomal variations.

We rate this claim False.

UPDATE, Feb. 21, 2025: This fact-check has been updated to include a post-publication comment from Mace's office.

Imprinting And Genetic Disease: Angelman, Prader-Willi And Beckwith-Weidemann Syndromes

Figure 1: Andrew, a child with Angelman syndrome.

Angelman syndrome (Figure 1) is a disorder of the nervous system characterized by developmental disabilities, seizures, speech deficits, and motor oddities. The disease is named after English physician Harry Angelman, who in 1965 happened to see three children who shared a curiously similar constellation of symptoms. Angelman referred to these children as "happy puppets" because of their smiling, laughing demeanor and their jerky gait, and he published a report on his findings (Angelman, 1965). Shortly thereafter, diagnoses of Angelman syndrome began to rise. Today, the disorder is known to occur in approximately one in every 15,000 to 20,000 people, and it has been reported all over the world.

Despite the widespread prevalence of Angelman syndrome, the chromosomal abnormality underlying this disease remained unknown for several decades following Angelman's initial report. Eventually, however, thanks to advances in research methods, a deleted area in chromosome 15 was detected (Figure 2; Magenis et al., 1987); this deletion occurs in about 70% of Angelman patients. Although the deletion appears to be extremely small (and therefore hard to detect), it is quite significant. This deletion, which is believed to be about 4 million base pairs in length, includes a gene involved in the ubiquitin pathway known as UBE3A, for which the maternal gene is normally expressed while the paternal gene is silenced. The loss of that maternal contribution, by either deletion (as in 70% of Angelman patients) or other genetic abnormalities (in the other 30% of cases), results in the phenotypic symptoms observed in Angelman syndrome. Here, the paternal gene cannot fill in the blank because it has been turned off by imprinting (Figure 2). Note that there have also been rare cases in which the maternal allele has been lost completely, resulting in two copies of this gene from the father (a condition known as uniparental disomy). Moreover, if the maternal locus is errantly imprinted, this too can result in Angelman syndrome.

The region of chromosome 15 that is involved in Angelman syndrome also contains another important gene that is imprinted the other way. In this case, when the paternal contribution is lost, the result is a condition known as Prader-Willi syndrome (PWS). PWS patients suffer from extreme feeding problems, including hyperphagia, or extreme, insatiable appetite and obsession with food. Affected children are also developmentally delayed for motor skills due to decreased muscle tone. As previously mentioned, PWS is caused by the loss of other genes in this same region, including SNRPN. This gene, normally active from the paternal copy of chromosome 15, encodes a component of mRNA splicing.

In short, imprinting of the same region on chromosome 15 has been implicated for both Angelman and Prader-Willi syndromes. However, it is the loss of the maternal contribution that is linked to Angelman syndrome and the loss of the paternal contribution that is linked to PWS. In each case, the presence of a second good copy of the gene(s) on the methylated, tightly packed copy of chromosome 15 is of no use in correcting the defect.

Figure 2: Genetic mechanisms leading to Angelman syndrome.

The rectangles represent chromosome 15. Hatched chromosomes have a paternal pattern of gene functioning and DNA methylation; open chromosomes have a maternal pattern. Angelman syndrome is caused by a large deletion of the region of the maternal chromosome that contains UBE3A, or by a DNA sequence change (mutation) in the UBE3A gene inherited from the mother. The condition can also be caused by inheritance of two normal copies of UBE3A from the father, with no copy inherited from the mother. Other AS individuals inherited chromosome 15 from their mother, but that chromosome had the paternal pattern of gene function and DNA methylation.

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