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Coffin-Lowry syndrome

Mode of Inheritance

Coffin-Lowry syndrome (CLS) has an X-linked Dominant pattern of inheritance. A genetic condition that is inherited via a dominant pattern requires only one copy of the mutated allele to cause the disease. An X-linked disease has the disease causing gene on the X sex chromosome. CLS affects males more than females

Symptoms

Multiple parts of the body can be affected in an individual that has Coffin-Lowry syndrome. Males are affected more often than females are, and their symptoms include severe intellectual disability and also delayed development of the mind and body for males and women can also have intellectual disability but more often than not are cognitively normal. When an individual with CLS is at a young age in life, they may experience collapsing episodes if they are startled or if their is a loud sudden ruckus and these episodes are known as stimulus-induced drop episodes. Unusual facial features may also be a distinct symptom of CLS. These facial features can include a larger forehead than normal, eyes that are spaced further apart than normal, and also a wider mouth than normal. Other physical features that can appear also include short fingers and a shorter height than most, usually a smaller head and also major curvature of the spine.

Therapy and Treatment

Symptomatic treatment exist for Coffin-Lowry syndrome entailing both physical and speech therapy.

Discovery of Gene

Using genetic linkage analysis, the defective RPS6KA3 gene was discovered in 1996 to be on the X chromosome, specifically Xp22.2. Using RT-PCR and Southern blot hybridization, the initial screening compared genomic DNA in 76 unrelated CLS patients, plus 1 normal control individual.

Types of Mutations

Loss of function mutations in the Ribosomal Protein S6 Kinase Polypeptide 3 (RPS6KA3) gene are commonly responsible for CLS. There have been over 130 different mutations reported that are distributed throughout RPS6KA3 gene, showing strong allelic heterogeneity. Some mutations have been shown to interfere with the recognition of splicing sites, which can cause partial or complete exon skipping of the RPS6KA3 gene. Other types of mutations can be caused by an amino acid substitution, or missense mutation. The missense mutation alters the stability of the RSK2 protein, which decreases the affinity with which ATP molecules bind to the protein. If the ATP molecules are unable to bind, this will likely lead to the loss of kinase activity in the RSK2 protein.

Causes

Coffin-Lowry syndrome (CLS) is caused by loss of function mutations in 90 kDa ribosomal S6 kinase gene (RPS6KA3). RPS6KA3 is located on the short arm of the X chromosome (Xp22.2) This gene has an open reading frame that is split into 22 exons that encodes a protein 740 amino acids in length known as the RSK2 protein. RSK2 is a serine-threonine protein kinase that belongs to a family of kinases, RSK1-RSK4, that share highly conserved functional kinase catalytic domains that are linked together by a regulatory linker region. One of the functions of RSK2 is to act as an upstream signaling element in the activation pathway of phospholipase D1 (PLD1) which controls the production of fusogenic lipids that are required for calcium-regulated exocytosis. In response to a neuron growth factor (NGF), RSK2 activates PLD1 by phosphorylating its Thr147 residue. This activation pathway is thought to be involved in the later stages of neurite outgrowth that are critical for the establishment of neuronal networks during brain development. The defects in PLD1 and fusogenic lipid synthesis due to loss of function of the RSK2 protein could explain the abnormal growth and development of neural circuits that is seen in CLS patients. However despite extensive research on CLS, the underlying relationship between genotype and phenotype remains poorly understood.

Frequency

The estimated incidence of occurrence is 1 in 40,000-50,000 people. The majority of affected individuals are males, and males typically have a more severe phenotype than females. Many women who are mildly affected will go undiagnosed or will not be diagnosed correctly.

Genetic Testing

For patients displaying signs of Coffin-Lowry Syndrome genetic testing is available. Sequence analysis of the coding region of the RPS6KA3 gene is performed; mutations in this gene can confirm diagnosis of Coffin-Lowry Syndrome. Sequence analysis can identify point mutations and splice site variants but is not reliable for detection of deletions or insertions. If no mutation is seen in sequence analysis, deletion/duplication analysis will then be performed. For research purposes, ribosomal S6 Kinase enzyme activity is studied when a mutation can not be identified. Enzyme activity is not measured in females because it is unreliable for confirming diagnosis.

Future Directions

According to the website ClinicalTrials.gov and the National Institute of Neurological Disorders and Stroke, there are currently no clinical trials being done for the prevention or syndrome specific treatment of Coffin-Lowry Syndrome.