Periaxin mutations cause recessive Dejerine-Sottas neuropathy

Abstract

The periaxin gene (PRX) encodes two PDZ-domain proteins, L- and S-periaxin, that are required for maintenance of peripheral nerve myelin. Prx(-/-) mice develop a severe demyelinating peripheral neuropathy, despite apparently normal initial formation of myelin sheaths. We hypothesized that mutations in PRX could cause human peripheral myelinopathies. In accordance with this, we identified three unrelated Dejerine-Sottas neuropathy patients with recessive PRX mutations-two with compound heterozygous nonsense and frameshift mutations, and one with a homozygous frameshift mutation. We mapped PRX to 19q13.13-13.2, a region recently associated with a severe autosomal recessive demyelinating neuropathy in a Lebanese family (Delague et al. 2000) and syntenic to the location of Prx on murine chromosome 7 (Gillespie et al. 1997).

Figure 1

Mapping of PRX and expression of PRX mRNA. a, By ePCR, BAC CTC-492K19, which contains PRX, maps between D19S324 and D19S223. We confirmed this by metaphase FISH; cohybridization with BAC RPCI-11 104E13 (red) and chromosome 19 control cosmid F13141 (green) assigned PRX to 19q13.13-q13.2 (arrow, ideogram in accord with the International System for Human Cytogenetic Nomenclature [1995]). b, Diagram showing the two PRX mRNAs resulting from alternative retention of intron 6. The large periaxin protein (L-PRX) is encoded by the shorter spliced mRNA, and the smaller periaxin protein (S-PRX) is encoded by the longer mRNA retaining intron 6. Coding regions are shaded. c, Northern analysis showing that both the 5.1- and 5.6-kb PRX mRNAs were most abundant in spinal cord, a tissue with many peripheral nerve roots.

Figure 2

Comparison of human, murine, and rat L-periaxin (a) and S-periaxin (b) amino acid sequences. a, Human L-periaxin has ∼78% and ∼73% sequence identity with the murine and rat proteins, respectively. The PDZ domain, tripartite nuclear localization signal (NLS1, NLS2, and NLS3), repeat domain, and acidic domain previously characterized in mice and rats are conserved in humans. Arrowheads indicate mutations identified in patients. b, S- and L-periaxin share a common amino terminal, but retention of intron 6 in the mRNA encoding S-periaxin results in a truncated protein with 20 amino acids encoded within the intron (blackened box). Identical amino acids are indicated by a colon (:), gaps by a dash (—) and stop codons by an asterisk (*).

Figure 3

Chromatograms of PRX alterations identified in three families. Families HOU297, HOU579, and HOU418 exhibit autosomal recessive inheritance. Blackened symbols indicate DSN. Patient 851, from family HOU297, is compound heterozygous for mutations S929fsX957 and R953X; her older unaffected son is heterozygous for R953X (data not shown). Patient 1461, from family HOU579, is compound heterozygous for mutations V763fsX774 and R368X; her unaffected brother is heterozygous for V763fsX774 (data not shown). Patient 1136 from family HOU418 has the homozygous mutation S929fsX957; her two unaffected sisters and her son are heterozygous for this mutation (data not shown).

Figure 4

Mutations identified in PRX. The location of mutations within L-periaxin is indicated in the diagram at the top by the arrows. The clinical phenotype of each patient, their mutations, and the frequency of their mutations in North American control chromosomes are listed below.