Osteoporosis is a disease of the bone; which makes the bones abnormally dense and prone to fractures. There are different kinds of Osteoporosis, differ by their pattern of inheritance and the severity of their signs and symptoms. There are typically three types of osteopetrosis; autosomal dominant osteopetrosis (ADO), autosomal recessive osteopetrosis (ARO) and intermediate autosomal osteopetrosis (IAO).
Autosomal dominant osteopetrosis is typically the less harsh type of the disorder and most common. It affects about 1 out of 20,000 people in the population. In this form, some of the affected individuals show no signs and symptoms. However, in affected individuals who develop signs and symptoms, the major features of the condition include abnormal side-to-side curvature of the spine (scoliosis) or other spinal abnormalities, multiple bone fractures, a bone infection called osteomyelitis, and arthritis in the hips. These problems usually become apparent in late childhood or adolescence.
The autosomal recessive osteopetrosis, where about 1 in 250,000 individuals are affected; is a more severe form of the disorder that becomes apparent in early childhood. Affected individuals have a high risk of bone fracture resulting from seemingly minor bumps and falls. Their abnormally dense skull bones pinch nerves in the head and face (cranial nerves), often resulting in vision loss, hearing loss, and paralysis of facial muscles. Dense bones can also impair the function of bone marrow, preventing it from producing new blood cells and immune system cells. Therefore, people with this form of the disorder (severe form) are at risk of abnormal bleeding, a shortage of red blood cells (anemia), and recurrent infections. In the most severe cases, these bone marrow abnormalities can be life-threatening in childhood.
Other symptoms of ARO can include dental abnormalities, an enlarged liver and spleen (hepatosplenomegaly), and slow growth and short stature. Depending on the genetic changes involved, people with severe osteopetrosis can also have brain abnormalities, intellectual disability, or recurrent seizures (epilepsy).
The rare form of osteopetrosis is the intermediate autosomal osteopetrosis, a form which can either be an autosomal dominant or an autosomal recessive pattern of inheritance. Individual with this form of the disorder normally do not have life-threatening bone marrow abnormalities. However, some affected individuals have had abnormal calcium deposits (calcifications) in the brain, intellectual disability, and a form of kidney disease called renal tubular acidosis. The signs and symptoms of this condition become noticeable in childhood and include an increased risk of bone fracture and anemia.
Gene
The CLCN7 gene belongs to the CLC family of genes, which provide instructions for making chloride channels. These channels, which transport negatively charged chloride ions, plays a key role in a cell's ability to generate and transmit electrical signals. Some CLC channels regulate the flow of chloride ions across cell membranes, while others transport chloride ions within cells.
The CLCN7 gene provides instructions for making a chloride channel called ClC-7. These channels are abundant in cells throughout the body. They are particularly important for the normal function of osteoclasts, which are specialized cells that break down bone tissue. Osteoclasts are involved in bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. Bones are constantly being remodeled, and the process is carefully controlled to ensure that bones stay strong and healthy.
ClC-7 channels help regulate the relative acidity (pH) of osteoclasts. These channels transport two negatively charged chloride ions out of these cells for every positively charged hydrogen atom (hydrogen ion) that flows in. In this way, ClC-7 channels help balance the acidic environment that osteoclasts use to dissolve bone tissue. The pH inside and outside osteoclasts must be carefully controlled for these cells to break down bone effectively.
The CLCN7 gene is located on the short (p) arm of chromosome 16 at position 13. More precisely, the CLCN7 gene is located from base pair 1,494,934 to base pair 1,525,084 on chromosome 16.
Gene Structure
Table with Exon/Intron/UTRs
Promoter site(s)
Gene Expression (where & when is it expressed)
Gene Regulation (how is expression controlled, feedback
mechanisms etc.)
Alternatively Spliced forms (if any, why are they important?)
RNA regulation (i.e. start sites, half-life, siRNAs etc.)
Polyadenylation sites
Protein sequence (& Protein ID)
Structural/Functional domains within polypeptide
Form of protein (i.e. monomer, homodimer, heterodimer etc.)
Functional Motifs (Prosite http://www.expasy.ch)
Post-translational modifications
Alternative forms/isoforms
Protein half-life (degradation)
Structures of proteins that may be related
Other proteins or small molecules that may interact with your protein
Functional Information (pathways, networks, protein complexes)
Disease state(s) for which the gene is implicated
Discuss the nature of the disease (on a molecular basis what is going on), in terms of what you have learned about the control and function of the gene, the mRNA and the protein
What mutations associated with the disease?
Mutations in the CLCN7 gene impair the function of ClC-7 channels. This mutations are responsible for about 75 percent of cases of autosomal dominant osteopetrosis, 10 to 15 percent of cases of autosomal recessive osteopetrosis, and all known cases of intermediate autosomal osteopetrosis. The defective channels cannot transport chloride ions effectively, which disrupts the regulation of pH in osteoclasts. As a result, osteoclasts are unable to break down bone normally. When old bone is not broken down as new bone is formed, bones throughout the skeleton become unusually dense. The bones are also structurally abnormal, making them prone to fracture. These problems with bone remodeling underlie all of the major forms of osteopetrosis.
Conclusions & References
Santa Cruz Biotechnology.,
Osteopetrosis, http://ghr.nlm.nih.gov/condition/osteopetrosis
CLCN7, http://ghr.nlm.nih.gov/gene/CLCN7
