Am J Med Genet A. 2006 Feb 24; [Epub ahead of print]
NTNG1 mutations are a rare cause of Rett syndrome
Archer HL, Evans JC, Millar DS, Thompson PW, Kerr AM, Leonard H, Christodoulou J, Ravine D, Lazarou L, Grove L, Verity C, Whatley SD, Pilz DT, Sampson JR, Clarke AJ.
Abstract
A translocation that disrupted the netrin G1 gene (NTNG1) was recently reported in a patient with the early seizure variant of Rett syndrome (RTT). The netrin G1 protein (NTNG1) has an important role in the developing central nervous system, particularly in axonal guidance, signalling and NMDA receptor function and was a good candidate gene for RTT. We recruited 115 patients with RTT (females: 25 classic and 84 atypical; 6 males) but no mutation in the MECP2 gene. For those 52 patients with epileptic seizure onset in the first 6 months of life, CDKL5 mutations were also excluded. We aimed to determine whether mutations in NTNG1 accounted for a significant subset of patients with RTT, particularly those with the early onset seizure variant and other atypical presentations. We sequenced the nine coding exons of NTNG1 and identified four sequence variants, none of which were likely to be pathogenic. Mutations in the NTNG1 gene appear to be a rare cause of RTT but NTNG1 function demands further investigation in relation to the central nervous system pathophysiology of the disorder. (c) 2006 Wiley-Liss, Inc.
Lay Summary
A mutation in the gene for a protein called netrin G1 (NTNG1) was recently discovered in a single patient with a variant form of Rett syndrome with early seizure occurrences. In this paper, the authors continue the search and describe other NTNG1 mutations in other Rett syndrome patients. Briefly, they investigated 115 patients with Rett syndrome, but with no known mutations in MeCP2. Amongst this population, they identified four patients with alterations in the DNA sequence for the NTNG1 gene. However, it is noted that these mutations are "conservative" in nature - that is, the mutations change the DNA code, but do not change the resulting translated protein structure and/or function. As a result, the four mutations found here are not suspected to be the cause of Rett syndrome in these patients. However, the authors point out that as proper NTNG1 function is important for normal brain development, it remains an interesting candidate gene for further investigation.