Gonosomal mosaicism of a novel heterozygous mutation of P0 causes Charcot-Marie-Tooth neuropathy type 1B with apparent autosomal recessive inheritance

Charcot-Marie-Tooth neuropathy type 1 (CMT1) is the most common inherited demyelinating neuropathy. It has autosomal dominant inheritance associated with heterozygous mutations in the genes coding the peripheral myelin protein 22 (PMP22), the myelin protein zero (P0) and the early growth response 2 (EGR2) transcription factor. More severe, usually sporadic de-hypomyelinating neuropathies of infancy are classified as Dejerine-Sottas syndrome (DSS). Since the original description by Dejerine and Sottas of two affected siblings born of unaffected parents, DSS has long been considered to be autosomal recessive, but it is now known that DSS is also caused by heterozygous mutations that originate de novo in the forementioned genes. True autosomal recessive, usually severe, demyelinating neuropathies are rare and associated with still unknown genes. Two sisters born of unaffected parents suffered from a severe de-remyelinating neuropathy of infancy consistent with CMT1. Both patients carried a novel heterozygous G308→A transition of P0 without any additional mutation of PMP22 and EGR. The mutation is predicted to cause a Gly74→Glu substitution in the extracellular domain of P0 (P0ex). Gly74Glu is pathogenic because: it was absent in healthy controls; it changes a phylogenetically conserved residue; it is functionally non-conservative; based on the P0ex crystal, it is predicted to be structurally incompatible with the normal β-sheet conformation of P0ex. The healthy mother carried a minor proportion of the G308→A transition in white blood cells (=20 %), fibroblasts, buccal smear and hairs (=30%). We concluded that she is actually a gonosomal mosaic harboring clones of mutant somatic and germline cells. The Gly74→Glu substitution originated early in the embryogenesis of the mother, before the commitment to germ cells.