A chromosome is a tightly coiled structure found in the nucleus of nearly every cell, consisting of DNA wrapped around proteins. These structures organize genetic information, ensuring it is accurately replicated and distributed during cell division. Humans typically inherit 23 pairs of chromosomes, 22 pairs of autosomes and one pair of sex chromosomes, totaling 46. Chromosome 4 is one of these autosomes, carrying thousands of instructions that influence human biology and development.
Physical Characteristics of Chromosome 4
Chromosome 4 is the fourth largest human autosome. It is classified as a submetacentric chromosome, meaning its centromere is positioned slightly off-center. This offset divides the chromosome into one shorter arm, designated the “p” arm, and one longer arm, known as the “q” arm. The chromosome spans approximately 191 million base pairs, representing over 6% of the total DNA within a human cell. Estimates suggest that Chromosome 4 contains between 1,000 and 1,100 genes that encode proteins for diverse biological processes, including growth regulation and neurological function.
Genes Governing Normal Biological Function
The genes on Chromosome 4 orchestrate numerous routine processes necessary for the body’s normal operation. One example is the FGFR3 gene, which provides instructions for a protein that regulates cell growth and division. This protein is important in bone development, acting as a brake to limit the formation of bone from cartilage, a process called endochondral ossification.
For neurological health, the SNCA gene produces alpha-synuclein, a protein highly abundant in the brain, especially at the tips of nerve cells. This protein helps maintain the supply of synaptic vesicles, which store and release chemical messengers between neurons. Proper alpha-synuclein function is fundamental to the efficient relay of signals that control movement and other brain functions.
The chromosome also houses genes that direct immune surveillance and response. For instance, the CXCL family of genes encodes chemokines, which are small signaling proteins. These molecules guide specific immune cells like neutrophils to sites of injury or infection to initiate the defense process.
Single-Gene Disorders on Chromosome 4
When a single gene on Chromosome 4 undergoes a mutation, it can disrupt a fundamental biological process and lead to a disorder. The most widely known single-gene disorder linked to this chromosome is Huntington’s Disease (HD), caused by a mutation in the HTT gene located on the short arm. The disease mechanism involves an abnormal expansion of a trinucleotide repeat sequence, specifically CAG, within the gene.
In a healthy individual, the CAG segment is repeated a normal number of times, but in those who develop HD, this segment is repeated excessively. This expansion results in the production of an altered, toxic protein that gradually damages nerve cells in the brain, leading to uncontrolled movements, cognitive decline, and psychiatric disturbances. The number of CAG repeats directly influences the age of disease onset, with a higher number correlating with an earlier presentation of symptoms.
Another condition arising from a single-gene change is Facioscapulohumeral Muscular Dystrophy (FSHD), which involves an unusual mechanism at the end of the long arm. FSHD is associated with a contraction in a repetitive DNA sequence region known as D4Z4. This contraction causes the DNA in that region to become abnormally “unwound” or hypomethylated, meaning there are too few chemical tags attached to silence the gene.
The lack of silencing allows an adjacent gene, DUX4, to become active in muscle tissue, where it is normally switched off. The inappropriate production of the DUX4 protein is toxic to muscle cells, leading to progressive weakness and wasting, typically affecting the muscles of the face, shoulders, and upper arms.
A mutation in the FGFR3 gene on Chromosome 4 causes Achondroplasia, a form of short-limbed dwarfism. This mutation causes the receptor protein to be constantly active, excessively inhibiting the normal process of long bone growth.
Syndromes Caused by Structural Changes
Beyond single-gene mutations, large-scale structural changes to Chromosome 4 can affect numerous genes at once, leading to complex syndromes. Wolf-Hirschhorn Syndrome (WHS) is the most prominent example, resulting from a partial deletion of the short arm (the p arm). The loss of this segment, often designated as 4p-, removes many genes involved in fetal development.
The physical consequence of this large deletion is a characteristic set of features, including a distinctive broad nose and high forehead, often described as a “Greek helmet” appearance. Individuals with WHS commonly experience growth delays, severe intellectual disability, and muscle hypotonia. Seizures are also a frequent manifestation, and the severity of the syndrome is often related to the size of the deleted segment.
Other structural abnormalities, such as the duplication of a segment, can also cause developmental problems. Any deviation from having exactly two copies of each chromosomal region upsets the balance of gene activity.