Saturday, 28 April 2012

New Genetic Mutation found to cause rare Skeletal Dysplasia


Unlocking the secrets of various diseases has been one of the priorities throughout history; however, it has also been difficult and inefficient. Recently, there have been advancements in the understanding of a specific group of diseases based on a new approach in gene-mapping. Known as skeletal dysplasias and commonly referred to as dwarfism, it has caused abnormalities in the development of the skeleton. Symptoms associated with skeletal dysplasias include irregularly sized and shaped limbs which may render the body out of proportion (Cedars-Sinai 2012). Although it was known that the cause of the disease was genetic mutation and hereditary (Chen 2011), the gene responsible for activating the condition was not known.

Bone Deformities of MCTO (Zankl A, et al. 2012)
In order to find the disease-causing gene, gene mapping was required, except this was “expensive and time-consuming” (Davy 2011). Previously, the University of Queensland Diamantina Institute had spent a decade locating the gene causing a type of skeletal dysplasia. Therefore, “next-generation sequencing” was implemented (Davy 2011).

Gene-mapping can be likened to a road map, which displays important landmarks and guides the researchers to specific areas of interest. It involves locating the disease responsible for the disorder, in this situation, a form of skeletal dysplasia. Once a blood or tissue sample is obtained from the patient, the DNA is isolated and examined (National Human Genome Research Institute 2012). From examination, a gene found only in those affected may be attributed to the cause of skeletal dysplasias.

The UQDI team investigated the exomes, part of the human genome which is attributed to altering appearance (BGI n.d.), of the patients and compared them to the data from the international Human Genome Project (Davy 2011). Through this, the gene responsible was determined.

The specific disease was Multicentric Carpotarsal Osteolysis (MCTO) a rare skeletal dysplasia. Using ‘next-generation sequencing’ they found a cluster of mutations on a 51 base pair region of the single exon of MAFB (Zankl A, et al. 2012). This gene encodes for a transcription factor which negatively regulates osteoclastogenesis, the development of osteoclasts which removes bone tissue. This is essential for normal renal development. They then used a program to assess how these mutations could have affected the corresponding protein. From this, it was realised that the mutations were probably causing the damage. According to Zankl et al. (2012), ‘MAFB is known to play critical roles in both osteoclast differentiation and activation and renal development, consistent with the major phenotypic features of MCTO’. Sanger sequencing, involving dideoxynucleotides was used to validate the sequences observed.

Sanger Sequencing of MAFB gene (Zankl A, et al. 2012)
This step forward in disease-gene mapping provides many advantages. For one, it helps in producing a cure. As the gene responsible for the condition is known, a corresponding cure can be developed to combat future cases. Drug development for treatment along with detection of skeletal dysplasia development before symptoms occur may also be possible (US Department of Energy 2011).

Advances in gene-mapping have opened up new doors but there’s still a long way to go. With possible treatments available for those in need, this may be the way forward in extending the wonder of human life.

Reference List

BGI n.d., Exome Sequencing, viewed 16 March 2012, <>.

Cedars-Sinai 2012, Skeletal Dysplasia, viewed 14 March 2012, <>.

Chen H 2011, Skeletal Dysplasia, viewed 10 March 2012, <>.

Davy, C 2011, ‘Gene-Mapping Advances’, Discovery at UQ 2011, pp. 19.
National Human Genome Research Institute 2012, Genetic Mapping, viewed 16 March 2012, <>.

US Department of Energy 2011, Medicine and the New Genetics, viewed 17 March 2012, <>.

Zankl A, Duncan E.L, Leo P.J, Clark G.R, Glazov E.A, Addor M, Herlin T, Kim C.A, Leheup B.P, McGill J, McTaggart S, Mittas S, Mitchell A.L, Mortier G.R, Robertson P.R, Schroeder M, Terhal P & Brown M.A 2012, ‘Multicentric Carpotarsal Osteolysis Is Caused by Mutations Clustering in the Amino-Terminal Transcriptional Activation Domain of MAFB’, The American Journal of Human Genetics, vol.90, no.3, pp.494-501.

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