A chromosome is a highly organized package of DNA, and humans typically possess 23 pairs, with one copy of each pair inherited from each parent. Chromosome 15 is a medium-sized autosome, spanning approximately 102 million DNA building blocks, which accounts for over three percent of the total DNA found in human cells. It is estimated to contain around 630 genes that provide instructions for a vast array of proteins and functions throughout the body. Its genetic landscape is notable for containing complex gene clusters, including a region susceptible to genetic rearrangements that can lead to distinct neurodevelopmental disorders.
The General Functions of Chromosome 15 Genes
The genes distributed across Chromosome 15 contribute to a wide spectrum of physiological processes, ranging from connective tissue structure to brain activity regulation. Several genes are instrumental in neurological development and function, including those that encode subunits for the GABA-A receptor, the brain’s primary inhibitory neurotransmitter system. Mutations in these receptor genes can affect neuronal signaling and have been associated with conditions like epilepsy and developmental delays.
The chromosome also plays a role in metabolism and maintaining the body’s connective framework. For instance, the FBN1 gene provides instructions for making Fibrillin-1, a protein that forms microfibrils, components of connective tissue throughout the body. A portion of the FBN1 gene sequence also produces asprosin, a metabolic hormone that regulates glucose and fat metabolism. Pigmentation is another function governed by genes on Chromosome 15.
The Unique Mechanism of Genomic Imprinting
A defining feature of Chromosome 15 is a cluster of genes subject to genomic imprinting, a process where only one copy of a gene, either maternal or paternal, is expressed. This silencing is achieved through epigenetic tags, primarily DNA methylation, which attach to the gene’s regulatory region and prevent it from being transcribed into a protein. The body relies entirely on a single, functional copy of the imprinted gene from a specific parent.
For example, some genes in the 15q11-q13 region are active only when inherited from the father, while others are active only when inherited from the mother. A small area within this cluster, known as the imprinting center, controls the methylation status for the entire region and ensures the correct parent-specific expression pattern is maintained. If the one active copy of an imprinted gene is damaged or missing, there is no backup copy to compensate, directly leading to a loss of function. This makes the imprinted region of Chromosome 15 particularly vulnerable to genetic errors. The resulting disorder depends entirely on which parent’s copy was affected, as the maternal and paternal chromosomes carry different sets of active genes in that location.
Syndromes Caused by Imprinting Errors and Deletions
The parent-of-origin effect results in two distinct neurodevelopmental conditions, Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS), which arise from genetic errors in the same 15q11-q13 region.
Prader-Willi Syndrome (PWS)
PWS occurs when the paternal contribution to this region is absent or non-functional, often due to a deletion of the paternal chromosome copy. This loss of paternally expressed genes, such as the cluster of SNORD116 genes, results in a lack of certain proteins. PWS is characterized in infancy by hypotonia (poor muscle tone) and feeding difficulties, followed in early childhood by an insatiable hunger, known as hyperphagia. This constant drive to eat results from a dysfunction in the brain’s satiety signals and can lead to severe obesity if food access is not strictly managed. Individuals with PWS also experience mild to moderate intellectual disability and behavioral challenges.
Angelman Syndrome (AS)
Angelman Syndrome results from the loss of the maternally expressed genes in the same region, most notably the UBE3A gene. This gene encodes a protein involved in the ubiquitin pathway, which tags other proteins for degradation, a process particularly important in neurons. When the maternal copy of UBE3A is mutated or missing, AS results because the paternal copy is naturally silenced by imprinting in the brain. The clinical presentation of AS includes severe developmental delay, a lack of speech, and problems with balance and movement, often causing a characteristic walking gait. Individuals with AS frequently exhibit a behavioral phenotype, including a happy, excitable demeanor, frequent laughter, and a fascination with water. Both PWS and AS can also be caused by inheriting two copies of Chromosome 15 from one parent (uniparental disomy) or a defect in the imprinting center itself.
Other Significant Conditions Linked to Chromosome 15
Beyond the complex imprinting disorders, Chromosome 15 is home to genes whose simple mutations cause other well-defined conditions unrelated to the parent-of-origin effect.
Marfan Syndrome
Marfan Syndrome is a connective tissue disorder caused by mutations in the FBN1 gene. Since Fibrillin-1 is a component of microfibrils, its mutation results in abnormalities in the skeleton, eyes, and cardiovascular system. This condition most seriously manifests as a weakening of the aorta.
Oculocutaneous Albinism Type II (OCA2)
OCA2 is caused by mutations in the OCA2 gene. This gene provides instructions for the P protein, which is thought to be involved in regulating the acidity within melanosomes, the structures where the pigment melanin is produced. A non-functional P protein disrupts melanin production, leading to hypopigmentation of the skin, hair, and eyes, along with associated vision problems.