Emberger syndrome is a very rare genetic disorder characterised by primary lymphoedema generally confined to the lower limbs and genitals and myelodysplasia associated with a greatly increased risk of acute myeloid leukaemia (AML). Although most cases are sporadic, familial cases do occur and it is known to be inherited as an autosomal dominant trait with incomplete penetrance. Other symptoms may include immunological abnormalities (particularly a low CD4/CD8 ratio), severe cutaneous warts, and deafness. Although many genes have been found to be mutated in subsets of AML, an inherited predisposition to this disease is very infrequent, and studying the genetic basis of conditions such as Emberger syndrome can be expected to lead to an increased understanding of the molecular mechanisms of AML development more generally.

A group of mainly UK-based researchers led by Sahar Mansour of St. George's, University of London, UK has now sequenced the complete exomes, or protein-coding genomes, of eight unrelated individuals with Emberger syndrome. Six of these were sporadic cases with the other two coming from families with a history of the condition. The clinical presentation of the cases ranged from minimal oedema and slight immunological abnormalities through to severe oedema, myelodysplasia and death from AML before late adolescence. This analysis highlighted a single gene, GATA2, as being mutated in each of these individuals, thus identifying it as a strong candidate gene for this disorder.

The researchers then confirmed their findings by sequencing this gene in these eight individuals and in the affected relatives of the two familial cases using the Sanger method. Each individual was found to have a heterozygous mutation in GATA2, with the same mutation occurring in all cases within each of the two families studied. In total, eight different mutations were identified, none of which was observed in the sequences of any of 300 unrelated control chromosomes. The mutations involved were predicted to lead either to premature protein termination or to disruption of the function of a critical domain.

The protein encoded by GATA2 is a member of a family of transcription factors that bind to DNA through two adjacent zinc-finger domains and that control the transcription of genes involved in the development of many tissue types. Mutations of GATA family transcription factors, including GATA2, have previously been identified in several cancers, and mutations in GATA2 itself have been identified in samples of leukaemic cells from patients with chronic myeloid leukaemia. One study identified a microdeletion of a region of chromosome 3 including GATA2 in an individual with multiple congenitial abnormalities who developed meylodysplasia by the age of 11. Mutations of this gene have also been found in patients with other defects of the lymphatic system.

Taken together, these findings further implicate GATA2 as a gene crucial for the development and maintenance of the lymphatic system. The identification of GATA2 haploinsufficiency as a primary cause of Emberger syndrome will not only help in the diagnosis and monitoring of this condition but will aid our understanding of the molecular mechanisms underlying AML development more generally.

Reference

Ostergaard, P., Simpson, M.A., Connell, F.C. and 17 others (2011). Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nature Genetics, published online ahead of print 4 September 2011. DOI: 10.1038/ng.923