Growth Disorders
Research in to gene mutations that cause a child to be born with marked short stature
Overview
Around 5000 children in the North-West will be affected by very marked short stature. Our research looks into the causes of such short stature and whether they are related to a hormonal deficiency, resistance to hormones or a fundamental problem with tissues in the body preventing normal growth and if they are related to a genetic problem. We are also working al
ongside partners in the pharmaceutical industry to look at genetic markers that affect how children respond to treatments to improve growth.
We want to be able to provide parents with a reason why their child is so short and make sure their child gets the best result out of growth hormone treatment.
Problem
Although there are a number of recognised conditions that slow growth, both in the womb and after birth, for many babies the cause is still unknown. We are investigating one particular disorder called 3-M syndrome, an autosomal recessive primordial growth disorder.
3-M syndrome is characterized by small birth size in the absence of recognisable maternal or placental pathology and resulting in significant proportionate short stature. The syndrome is also associated with distinct facial features (flat maxillae, prominent forehead), radiological abnormalities (tall vertebrae, slender long bones) and normal intelligence. Final adult height is in the range of 115 to 150 cm.
Our researchers have now found three genes, two of which were not previously known to have any effects on growth, that all cause 3-M syndrome. These genes code for proteins with very different functions, but in children they all result in the same problem – extremely poor growth. We are therefore describing a brand new pathway that controls human growth.
What we have achieved to date
By looking at the 3-M syndrome gene in very short children across the world our researchers have found that mutations in the CUL7 gene cause 3-M syndrome including truncating, nonsense and missense variants.
We know that reduction or absence of CUL7 has a major impact on growth and cell division; but the precise mechanisms by which this occurs remain unclear. CUL7 has an N-terminal binding domain for the tumor suppressor p53, and microRNA knock-down leads to inhibition of cell cycle progression mediated by p53. CUL7 also interacts with IRS-1, a downstream component of the signaling pathways of the insulin, IGF-I and GH receptors. Mouse embryonic fibroblasts derived from Cul7 knockout mice demonstrate accumulation of IRS-1, increased activation of Akt and MAPK pathways and ultimately poor cellular growth and senescence.
We have identified 11 probands with the 3-M phenotype in whom direct sequencing failed to detect CUL7 mutations. Two were from multiple affected families comprising of four and three affected individuals respectively, that were shown not to be linked to the CUL7 locus, demonstrating that 3-M syndrome is genetically heterogeneous. We have hypothesized that identification of further causative genes might shed light on a shared biochemical pathway controlling mammalian growth.
Autozygosity analysis was undertaken on one family and identified two regions shared by all four siblings on chromosome 2 (2q35-37.1), with a smaller critical region being shared by all three affected individuals in one of the other families.
Haplotype analysis amongst the probands homozygous for this region demonstrated a shared haplotype extending over 1.3 Mb and containing 60 known and hypothetical genes, none an obvious candidate for 3-M syndrome. Pathogenic variants were finally identified in OBSL1, encoding the cytoskeletal linker protein obscurin-like 1.
What we aim to achieve
In total, we identified eight different OBSL1 gene mutations in 18 patients from 10 families all predicted to result in premature protein truncations. OBSL1 is homologous to obscurin, which is a muscle protein localized to sarcomeres implicated in cell signaling. Obscurin interacts with titin and myomesin, proteins involved in anchoring myosin filaments at the M-band in myocytes and both titin and myomesin also interact with OBSL1. Expression of OBSL1 has been demonstrated in human heart and skeletal muscle. However, patients with mutations in OBSL1 were not found to have cardiovascular or muscular symptoms and it is possible that the overlapping ability of both OBSL1 and obscurin to bind titin and myomesin provides a degree of redundancy to explain this.
We believe that the identification of pathogenic mutations in the OBSL1 gene in 3-M syndrome represents the first identification of the role of a cytoskeletal adaptor protein in growth.
