Chromosomal Abnormalities and Gene Mutations
From Holoprosencephaly
Chromosomal Abnormalities and Gene Mutations associated with Holoprosencephaly
1. Are genetic and inherited the same thing?
No. A genetic disorder is one that involves a faulty gene. Inherited means a gene that is passed from one generation to the next. It is possible to have a genetic disorder caused by a new mutation to a gene that is not inherited from the previous generation.
2. What are chromosomes?
Human beings have 46 chromosomes in a set of 23 pairs. The chromosomes are different sizes and shapes and the contain the genes that act as a "blueprint" for how a person develops. The genes are all mixed up together on the chromosomes such that a gene for determining hair color may be right next to a gene taht influences brain development. Each cell in the body contains all 46 chromosomes with the exception of the eggs and sperm which are special. They have gone through a special kind of cell division to get only one copy of each chromosome in each cell. This is so that when they meet and join together to make a baby, you end up with one copy of each chromosome, and therefore, one copy of each gene, from each of your parents.
Approximately 25-50% of patients with HPE have chromosomal abnormalities. Most commonly, the abnormality is on chromosome 13, 18, 7, 3, or 21. The abnormality may be new in the patient or inherited from the parents.
3. What is a gene?
Genes are tiny, invisible packets of biochemical information (DNA) taht direct how our bodies develop and function. We all inherit thousands of genes from our parents, arranged on 46 chromosomes. Genes turn on and off to control our growth, body chemistry and even the color of our hair and eyes. Most genes work correctly, but some do not. Sometimes they change and begin to work poorly or not at all. Changes can be caused by radiation or certain chemicals or by unexplained accidents within our cells. nearly 4,000 genetic diseases afflict human beings.
HPE caused by single gene disorders can be categorized as syndromic (about 20% of the patients) or nonsyndromic. Syndromic HPE can be autosomal recessive (Smith-Lemli-Opitz syndrome, Mecke syndrom, Genoa syndrom, etc) or autosomal dominant (Pallister-Hall syndrom, Kallmann syndrome, etc). Nonsyndromic HPE includes mutations in SHH, ZIC2, SIX3 and TGIF.
4. What is gene testing?
Now that scientists have identified the various genes that cause numerous disorders, doctors can test individuals for some diseases and malformations. Genetic diseaes are caused by a mutation or defects in a gene or set of genes. Some mutations do not cause disease because the mutations are repaired (our cells have mechanisms for repairing DNA if mistakes are made in the sequence or if the DNA is damaged). Because we get 2 copies of every chromosome (one from mom and one from dad), sometimes if one gene is mutant, the other copy can provide enough gene product for normal function. However, sometimes changes in the DNA can cause significant changes in the protein sequence and cause detrimental effects.
5. What are the gene mutations associated with holoprosencephaly?
Identifying the gene responsible for a specific disease is similar to finding a needle in a haystack. Actually, finding the gene is even more difficult, because even up close, the gene still looks just like another piece of hay. At least 12 different loci on 11 different chromosomes have been found to be associated with HPE. Among these, several distinct genes have been identified, including SHH (sonic hedgehog), ZIC2 (Homolog of Drosophila Odd-paired or OPA), TGIF (TG-Interacting Factor) and SIX3 (Homolog of Drosophila So). Sequence changes in SHH associated with HPE include insertions, deletions, missense, and nonsence mutations. All mutations reported to date in TGIF are missense. Mutations in ZIC2 are mostly frameshift or caused by alanine tract expansion and in SIX3, missense.
6. What is known about ZIC2 mutations?
ZIC2 was identified as a canditate for HPE based on the observation that chromosome deletions, especially in the critical region 13q32 (chromosome 13), result in brain malformations. Patients with deletions of this region typically have severe brain malformations which include HPE as well as encephalocele and others. Investigators found several patients with isolated HPE and normal chromosomes. The results of further investigation of these patients has established that ZIC2 mutations cause HPE.
The ZIC2 genes are a family of zinc finger transcription factor genes that were originally defined by their similarity to the Drosophila odd-paired gene (opa). Research has confirmed that ZIC2 is a dosage-sensitive gene with a critical role in central nervous system development. ZIC2 acts very early in CNS development. Altered levels of ZIC2 result in the failure to form midline CNS structures.
To date, three categories of ZIC2 mutations have been identified. In the first category, the ZIC2 mutations inactivate the required protein for normal CNS development. The mutations leads to frameshifts resulting in stop codons. Hence, the HPE is caused by ZIC2 loss of function.
A second category of ZIC2 mutation results in an expansion of a polyalanine repeat that creates a slightly larger protein with altered activity (the mutation results in frame insertion of 10 alanines expanding the polyalanine repeat region from 15 to 25 alanines).
In the third category, the ZIC2 mutation is the result of a parent as a mosaic carrier of the mutation.
In recent studies by Max Muenke with over 500 HPE patients, 3 to 4% of the patients had ZIC2 mutations. Of the mutations encountered, most were frameshift, some were caused by alanine tract expansions, and 3 of the cases had a parent as a mosaic carrier of the mutation. Most of the cases had either alobar or semilobar HPE with only one lobar patient and one middle interhemispheric fusion variant patient in the study. Although it is reported that about 85% of HPE patients in general have severe facial malformations, this study found that none of the ZIC2 patients had significant facial deformities.
