CHARACTERIZATION OF A NONSENSE MUTATION IN THE CERULOPLASMIN GENE RESULTING IN DIABETES AND NEURODEGENERATIVE DISEASE

We report here on the characterization of a mutation in the ceruloplas min gene in a 45 year old woman with insulin-dependent diabetes mellit us who presented with the recent onset of gait disturbance and dysarth ria. Physical examination revealed an ataxic gait, scanning speech and retinal degeneration. Magnetic resonance imaging of the brain was con sistent with increased basal ganglia iron content and laboratory studi es revealed a low serum iron concentration and no detectable serum cer uloplasmin. Nucleotide sequence analysis of the ceruloplasmin gene fro m this patient revealed a G to A substitution in exon 15 resulting in a nonsense mutation at amino acid 858 (Trp858ter). The patient's young er, neurologically asymptomatic brother was also found to be homozygou s for this mutation. Taken together the clinical and genetic data supp ort the concept of an essential and unique role for ceruloplasmin in h uman iron metabolism. Identification of this kindred extends the spect rum of ceruloplasmin gene mutations resulting in this autosomal recess ive, late-onset neurodegenerative disease and highlights the importanc e of recognizing aceruloplasminemia as a genetic cause of diabetes and neurologic disease.