The MPZ gene

MPZ (sometimes written as MP0) is the name of one of the genes involved in Dejerine-Sottas. The acronym stands for Myelin Protein Zero. Myelin protein-zero is the major structural protein of peripheral myelin.

Location

The MPZ gene is located at 1q22 (on the long arm of chromosome 1 at position 22).

From genotype to phenotype

Mutations in MPZ can cause Charcot-Marie-Tooth disease, type 1B, several forms of axonal Charcot-Marie-Tooth type 2, Dejerine-Sottas syndrome, congenital hypomyelinating neuropathy, and Roussy-Levy syndrome.

In 2 sibs with autosomal recessive DSS, Warner et al. (1996) identified homozygosity for a gly74 frameshift mutation in the MPZ gene (159440.0025). Ikegami et al. (1996) likewise observed the DSS phenotype with homozygosity for mutation in the MPZ gene. The findings are parallel to those found with homozygosity for the PMP22 gene (601097) in the cases reported by Killian and Kloepfer (1979), Lupski et al. (1991), and Kaku et al. (1993). The heterozygous parents presented with CMT1, whereas the homozygous children were more severely affected with DSS. These findings indicated the dosage sensitivity of the MPZ and PMP22 myelin genes and also supported the hypothesis that these clinical entities, CMT1 and DSS, represent variants of the same disease.

Hayasaka et al. (1993) found a mutation of the MPZ gene in a 7-year-old boy with delayed motor development, hypotonia, muscle weakness, and sensory disturbance thought to be typical of Dejerine-Sottas syndrome (145900), or hereditary motor and sensory neuropathy type III (HMSN3). The patient was case 1 of Tachi et al. (1984). Cysteine was substituted for serine-63 in the extracellular domain. The patient was heterozygous for the mutation, which was absent in the parents and in 100 unrelated healthy controls.

Hayasaka et al. (1993) identified a gly167-to-arg mutation in the transmembrane domain of MPZ in case 20 of Ouvrier et al. (1987); the patient was thought to have typical Dejerine-Sottas syndrome (145900) except that his spinal fluid protein level was not elevated. The patient was heterozygous for the mutation, which was absent in the parents and in 100 unrelated healthy controls.

In a sporadic case of Dejerine-Sottas syndrome (145900), Warner et al. (1997) identified 3 de novo point mutations in exon 3 of the MPZ gene. The point mutations occurred on the same allele and resulted in 3 amino acid substitutions: ile85 to thr, asn87 to his, and asp99 to asn. They were all novel mutations; therefore, it was difficult to predict what the phenotype of these mutations would be individually. The mechanism by which they produced a severe phenotype was also unclear. None of the mutations occurred at a CpG dinucleotide and there were no known similar sequences to participate in a gene conversion event. The spacing between the mutations (5 bp and 36 bp) suggested the occurrence of sequence alterations on different faces of the double helix, which may be less likely to result from a single contact by an interacting exogenous chemical mutagen. The patient was the offspring of a 36-year-old mother and a 46-year-old father. He was noted at 9 weeks of age to have moderate to severe hypotonia and weak tendon reflexes. At 2 years, he showed delay in motor development. He sat without support and could stand with assistance, but could not walk. He appeared to be advanced in mental development. Motor nerve conduction velocities at 1 year of age were markedly delayed with significantly low amplitude. There was no response from the medial plantar and sural nerves on sensory nerve conduction tests. Nerve biopsy showed variation in fiber size with reduced number of axons, hypomyelination, and sporadic onion bulb formation.

In 2 sibs with autosomal recessive DSS (145900), Warner et al. (1996) identified homozygosity for a gly74 frameshift mutation in the MPZ gene. The mutation, a 1-bp deletion, led to premature termination that predicted a truncated protein of only 87 amino acids. This truncated protein was presumably degraded and never reached the membrane. Therefore, this mutation probably constituted a loss-of-function allele. The consanguineous parents, who were heterozygous for the 1-bp deletion, had a mild neuropathy with features of CMT1B. The children presented with the phenotype of Dejerine-Sottas syndrome which behaved as a recessive trait in this family, as compared to the dominant inheritance in other families (e.g., 159440.0004). This phenotypic variation between the heterozygous and the homozygous state closely resembled that seen in Mpz knockout mice (Martini et al., 1995).

Alternative names

• Myelin glycoprotein P Zero (P0)
• Myelin protein, peripheral (MPP)