A new point mutation affecting the fourth transmembrane domain of PMP22 results in severe, de novo Charcot-Marie-Tooth disease

A novel T→G mutation in exon 4 of the PMP22 gene was identified heterozygously in a girl with severe, de novo CMT1A disease. Duplication of the chromosomal 17p11-12 region, encompassing the PMP22 gene, was ruled out. This is the only known mutation that specifically affects the human fourth transmembrane (TM) domain of PMP22. It results in a substitution of a non-polar amino acid by a polar one (Leu¹⁴⁷→Arg), similar to the nearby Gly¹⁵⁰→Asp substitution, underlying the severe Trembler phenotype in the mouse. These mutations suggest that the fourth TM domain plays a crucial role in the normal function of PMP22. The new mutation also augments previous observations that diseases caused by mutations in PMP22 are more severe than those caused by the duplication of 17p11-12.