Causes of Primordial dwarfism in humans
Primordial dwarfism is a group of human single gene disorders with growth failure. Mutations in RTTN and XRCC4 can cause Primordial dwarfism. It appeared that in individuals with a RTTN mutation, the ortholog of RTTN is truncated or sometimes even completely absent, which causes embryonic lethality or left-right asymmetry. A missense mutation can also be caused by this mutation because of an autosomal-recessive form of polymicrogyria. A missense mutation in XRCC4, was found, which could not resolve DNA damages by ionizing radiation. The DNA of the individuals were sensitive to DNA damage, therefor the cell numbers during development will decrease, causing a reduction in the head and body size.
Size is one of the biggest differences between species, which is already determined when embryogenesis starts. In other words, organs grow to size appropriate to the size of the entire organism. The entire size is set by the compound of cell number and cell volume. (Klingseisen & Jackson, 2011). The average length for adult women is 1,65 meter and for adult men is 1,74 meters. but that is not the case for everyone. Some people have an adult length of 1.47 meter, which is not considered as a normal length; those people have an unusual low stature and are most of the time suffering from Primordial dwarfism. Primordial dwarfism is a group of human single-gene disorders with affective global growth failure, which can have a genetic or just a medical cause(Klingseisen & Jackson, 2011). Most people with primordial dwarfism also have a smaller head size compared to their body size (Klingseisen & Jackson, 2011). However, it is still hard to categorize many individuals that have Primordial dwarfism based only on their phenotype, because it is not always possible with the diagnosis of the syndrome(Murray et al., 2015). The body size of a human being can be cutback just by a simple problem of regulating cell numbers that are produced during development, but the assurance of growth of the body size is in fact a complex with a combination of many factors. So to actually keep the same size, cells have to duplicate in mass before everycell division.(Klingseisen & Jackson, 2011). This does not always happen in people that are suffering from Primordial dwarfism. But there are other malfunctions that also influence their growth. In this article some mutations that cause growth failure will be discussed and if Primordial dwarfism has an affect on the brain.
The linkage of mutations in RTTN and Primordial dwarfism
According to research that has been done, there is a linkage between RTTN and Primordial dwarfism. RTTN also called rotatin is a protein coding gene, but apparently in organisms that have Primordial dwarfism the ortholog of RTTN is truncated or sometimes even completely absent, which causes embryonic lethality or left-right asymmetry. This research also revealed that RTTN usually acts upstream of the most left-right asymmetry proteins, but due to the mutation this is either lost or acts bilateral instead of unilateral in the lateral plate mesoderm. For this research two families have been examined, which have Primordial dwarfism, intellectual disabilities, a mild motoric delay and who have been tested negative on clinical exome sequencing. In the first family that was examined, the researchers found an intronic variation in the exon 23 of RTTN, which introduces a stop codon in the transcript that occurs prematurely. With this finding it was suggested that mutations in RTTN can cause Primordial dwarfism with growth retardation, but to confirm this result they had to identify the same mutations in the other family. Another family that was examined a few years later had a missense mutations. This missense mutation was caused by an autosomal-recessive form of polymicrogyria, a brain abnormality which is caused by abnormal neuronal organization in the human cortex. Because of this finding the researchers examined family one and two again and found the same mutation. After that finding it was confirmed that individuals with Primordial dwarfism caused by a mutation in RTTN are more likely to have a brain malfunction. Even though family one and two have more mutations, namely a truncation and a missense, than the other family with just a missense, the similarity in phenotype indicate that the missense mutations have the same effect. (Shamseldin et al., 2015).
Relation between XRCC4 mutations and Primordial dwarfism
Not only RTTN mutations but also XRCC4 mutations have a relation with Primordial dwarfism. XRCC4 is part of the NHEJ pathway, which is as a mechanism for template-independent restoration of double stranded DNA breaks. XRCC4 plays a role to ligate in this mechanism, because of the formation of a filament that wraps around the DNA end. Mutations were found in many parts of the NHEJ pathway, namely missense mutations in XRCC4. LIG4 and XLF, forms a complex with XRCC4. Mutations in LIG4 are caused by a biallelic truncation mutation. The individuals that were examined all had a LIG4 mutation and were heterozygous for the missense mutation Leu774, which is located within the XRCC4 binding motif. Because of this reason scientist had a hypothesis that there is a connection between LIG4 and XRCC4 that can affect the growth phenotype and thereby cause Primordial dwarfism. It was found that XRCC4 and LIG4 mutations both could not resolve DNA damages by ionizing radiation. The DNA of the individuals were sensitive to DNA damage, therefor the cell numbers during development will decrease, causing a reduction in the head and body size. Sometimes a developmental delay occurs, but not always. Even though XRCC4 and LIG4 encode the same protein complex, the individuals with the mutations will differ in phenotype. Individuals with a LIG4 mutation can for example develop pancytopenia, because of a depletion of the hematopoietic stem cell pool, but individuals with a XRCC4 mutation cannot (Murray et al., 2015).
Primordial dwarfism is a group of human single-gene disorders with extreme global growth failure, these growth failures are caused by different protein mutations, such as; a mutation in RTTN or XRCC4. In this article the focus lays on the mutations in RTTN and XRCC4 that caused Primordial dwarfism. Like we explained in the text, both mutations are different. If the mutation in RTTN is the cause of Primordial dwarfism, there is an intronic variation in the exon 23 of RTTN. This introduces a premature stop codon in the transcript, which causes growth retardation in the individuals with Primordial dwarfism, but like the researchers found out not only the growth is affected by the RTTN mutation. If there is a missense mutation in the gene that causes brain malfunctions. They came to this conclusion after they examined 3 families. (Shamseldin et al., 2015). A mutation in XRCC4 acts completely different. XRCC4 is part of the NHEJ pathway, which is as a mechanism for template-independent repair of double stranded DNA breaks. XRCC4 plays a role to ligate in this mechanism. The mutations in XRCC4 are namely missense mutations, but a biallelic truncation mutation in the LIG4 gene can also be the cause. To find out if this was true some individuals were examined. The researchers believed that there was a connection between the XRCC4 and LIG4 mutations that can affect the growth phenotype and thereby cause Primordial dwarfism. The finding was that XRCC4 and LIG4 mutations both could not resolve DNA damages by ionizing radiation. The DNA of the individuals were sensitive to DNA damage, and for that reason there a decrease in cell numbers will develop, which will cause a reduction in the head and body size (Murray et al., 2015). The conclusion that can be made now is that the mutations in RTTN and XRCC4 both cause the growth failure of individuals with Primordial dwarfism in different ways. These findings are of major importance because there are a lot of people suffering from Primordial dwarfism, in this way they at least know the reason they have it and can get more specific help. Hopefully there will be a solution for this disease one day, but for now further research is required to properly understand and eventually to find a solution for this disease.
Klingseisen, A., & Jackson, A. P. (2011). Mechanisms and pathways of growth failure in primordial dwarfism. Genes Dev, 25(19), 2011-2024. doi:10.1101/gad.169037
Murray, J. E., van der Burg, M., H, I. J., Carroll, P., Wu, Q., Ochi, T., . . . Bicknell, L. S. (2015). Mutations in the NHEJ component XRCC4 cause primordial dwarfism. Am J Hum Genet, 96(3), 412-424. doi:10.1016/j.ajhg.2015.01.013
Shamseldin, H., Alazami, A. M., Manning, M., Hashem, A., Caluseiu, O., Tabarki, B., . . . Alkuraya, F. S. (2015). RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans. Am J Hum Genet, 97(6), 862-868. doi:10.1016/j.ajhg.2015.10.012