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Bipolar Disorder - ANK3 and CACNA1C genes

Source: http://www.topnews.in/brain-speaks-paralysis-2273164 (Permission pending)

Bipolar Disorder

Bipolar disorder, or manic-depressive illness, is a long-term neurological disorder characterized by abnormal mood swings, changes in energy and activity levels, and a varying ability to perform everyday tasks (5). Patients with the disorder typically experience symptom development as late teenagers or young adults (5).  These symptoms consist of “mood episodes” that take the patient back and forth between mania and depression, or sometimes even both at the same time in “mixed episodes (5)."

Symptoms

Range of moods (5):

While not experiencing mood episodes, patients may not show symptoms, while others might still have remaining symptoms (5).

Types

The Diagnostic and Statistical Manual of Mental Disorders (DSM) categorizes bipolar disorder into four basic types(5):

• Bipolar I Disorder – manic or mixed episodes, seven days or longer, and depressive episodes, two weeks or longer
• Bipolar II Disorder – depressive episodes alternating with hypomanic episodes (no manic or mixed episodes)
• Bipolar Disorder Not Otherwise Specified (BP-NOS) – symptoms that do not exactly meet the characteristics defining bipolar I or II but that are abnormal in terms of mood and behavior
• Cyclothymic Disorder, or Cyclothymia – a mild form of the disorder characterized by hypomanic episodes alternating with mild depressive episodes for two years or more

Another category is called rapid-cycling bipolar disorder, which consists of a person having at least four episodes of major depression, mania, hypomania, or mixed symptoms within one year (5).

Associated or Co-existing Illnesses

The varied mood episodes associated with bipolar disorder may be misinterpreted as schizophrenia, which is characterized by delusions and hallucinations (5).

Many people with bipolar disorder show signs of substance abuse5. It is not known whether this is related to the disorder itself or whether it is simply due to patients using alcohol or drugs as a self-treatment initiative. Regardless, drug and alcohol abuse tend to prompt and/or increase bipolar symptoms (5).

Commonly co-existing illnesses, which may complicate a proper diagnosis of bipolar disorder, include post-traumatic stress disorder (PTSD), social phobia, and other anxiety disorders, attention deficit hyperactivity disorder (ADHD), thyroid disease, migraine headaches, heart disease, diabetes, obesity, and other physical illnesses (5).

Is the disorder genetically based?

If a child’s parent or sibling has bipolar disorder, that child is four to six times more likely to develop the disorder as well (5).

Researchers recognized the following traits as appearing to be hereditary: history of psychiatric hospitalization, co-occurring obsessive-compulsive disorder (OCD), age at first manic episode, and number and frequency of manic episodes (5).

While a gene may predispose an individual to the disorder, it does not guarantee it. Researchers studying identical twins (having all of the same genes) have found that one twin can develop the disorder without the other doing so as well (5).

Researchers using brain-imaging studies compared the brain development of children with bipolar disorder to children with  “multi-dimensional impairment,” which causes similar symptoms to those of bipolar disorder and schizophrenia (5).

ANK3

Figure 1: This is a Protein Data Bank (PDB) image of 1N0Q - 3ANK: a designed ankyrin repeat protein with three identical consensus repeats (secondary structure)
Source: RCSB Protein Data Bank. RCSB Protein Data Bank [Internet]. [modified 2011 Jan 25; cited 2011 Jan 31]. 3ANK: A designed ankyrin repeat protein with three identical consensus repeats. Available from: http://www.rcsb.org/pdb/explore/jmol.do?structureId=1N0Q&bionumber=1 (Permission pending)

The ANK3 gene, located on chromosome 10q21, encodes the protein Ankyrin-3 (ANK-3), part of the ankyrin family (3). Ankyrins are said to connect the integral membrane proteins to the underlying spectrin-actin cytoskeleton and they participate substantially in cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains3. The basic structure of an ankyrin protein consists of  three main substructures (3). These include an amino-terminal domain containing multiple ankyrin repeats, a central region with a highly conserved spectrin binding domain, and a carboxy-terminal regulatory domain which is the least conserved and subject to variation (3). Different isoforms of ankyrin, caused by alternative splicing, are expressed in other tissues and express affinities for different target proteins (3). The protein encoded by the ANK3 gene is the gene product from ankyrins 1 and 2, from which it is immunologically distinct (3). Researchers first located the gene at the axonal initial segment and nodes of Ranvier neurons in the central and peripheral nervous systems (3). By analyzing deletions of the protein, researchers found that it is necessary for the grouping of voltage-gated sodium channels at axon initial segments as well as for normal action potential firing (3).

CACNA1C

Figure 2: This is a Protein Data Bank (PDB) image of 2BE6 - 2.0 A crystal structure of the CaV1.2 IQ domain-Ca/CaM complex (secondary structure)
Source: RCSB Protein Data Bank. RCSB Protein Data Bank [Internet]. [modified 2011 Jan 25; cited 2011 Jan 31]. 2.0 A crystal structure of the CaV1.2IQ domain-Ca/CaM complex. Available from: http://www.rcsb.org/pdb/explore/jmol.do?structureId=2BE6&bionumber=1 (Permission pending)

The CACNA1C gene, located on chromosome 12p13, encodes an L-type, alpha-1 subunit of a voltage-dependent calcium channel (Cav1.2) (4). Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization (4). Cav1.2 is made up of 24 transmembrane segments and forms the pore through which ions pass into the cell (4).

References

1. Ferreira MAR, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. PubMed [Internet]. 2009 Jun 30 [cited 2011 Jan 23]; [1056-1058]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703780/.

2. Kua E, Reder M, Grossel MJ. 2004. "Science in the News: A Study of Reporting Genomics." Public Understanding of Science. 13: 309–322.

3. National Center for Biotechnology Information. ANK3 ankyrin 3, node of Ranvier (ankyrin G) [Homo sapiens]. Genes and mapped phenotypes [Internet]. 2011 Jan 11 [cited 2011 Jan 30]. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=288#

4. National Center for Biotechnology Information. CACNA1C calcium channel, voltage-dependent, L type, alpha 1C subunit [Homo sapiens]. Genes and mapped phenotypes [Internet]. 2011 Jan 11 [cited 2011 Jan 30]. Available from:http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=775

5. National Institute of Mental Health. [Internet]. Bethesda (MD): Bipolar Disorder; [modified 2010 Aug 31; cited 2011 Jan 23]. Available from: http://www.nimh.nih.gov/health/publications/bipolar-disorder/complete-index.shtml.

6. UniProtKB. Ankyrin-3-Homo sapiens (Human) [Internet]. [modified 2011 Jan 11; cited 2011 Jan 23]. Available from: http://www.uniprot.org/uniprot/Q12955.

7. Wade N. Gene hunt hints at cause of Bipolar Disorder. The New York Times [Internet]. 2008 Aug 18 [cited 2011 Jan 23]; [1]. Available from: http://www.nytimes.com/2008/08/15/science/15visual.html.

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