The PMP22 gene

PMP22 is the name of one of the genes that can cause Dejerine-Sottas. The acronym stands for Peripheral Myelin Protein 22. PMP22 is a major component of myelin expressed in the compact portion of essentially all myelinated fibers in the peripheral nervous system and is produced predominantly by Schwann cells. Studies in injured nerve suggested a role during Schwann cell growth and differentiation (Spreyer et al., 1991, Snipes et al., 1992).

PMP22 is expressed in cranial nerves but not in the mature central nervous system; however, during development it is expressed initially in all 3 germ layers and subsequently in migratory neural crest cells (Hagedorn et al., 1999; Wulf et al., 1999). These observations suggested that mutations in PMP22 might cause sensorineural deafness by demyelination of the eighth cranial nerve or by maldevelopment of the inner ear, which is a neural crest derivative, or by a combination of the 2. The rarity of severe deafness among families with PMP22 mutations suggests that most PMP22 mutations have minimal effects on inner ear development or cranial nerve myelination (Boerkoel et al., 2002).

Location

The PMP22 gene is located at 17p11.2 (on the short (p) arm of chromosome 17 at position 11.2).

From genotype to phenotype

Roa et al. (1993) identified point mutations in the PMP22 gene in patients with Dejerine-Sottas syndrome (DSS; 145900), a severe form of peripheral neuropathy with congenital, infantile, or juvenile onset (601097.0006). Although the change in PMP22 in Dejerine-Sottas syndrome is usually a point mutation or deletion, Silander et al. (1996) described duplication in PMP22 in patients who seemed to fit the clinical description of Dejerine-Sottas syndrome.

Dejerine-Sottas syndrome (145900) is characterized by hypertrophic, demyelinating neuropathy. Clinical symptoms are similar to but more severe than those of Charcot-Marie-Tooth disease type 1A (118220). By mutation analysis of the PMP22 coding region in 2 unrelated Dejerine-Sottas patients, Roa et al. (1993) identified individual missense point mutations present in the heterozygous state. In 1 family, both parents were negative for the mutations, suggesting that it was de novo in origin. One patient had a T-to-A transversion predicting a met69-to-lys substitution, whereas the other had a C-to-T transition predicting a ser72-to-leu substitution. The patient with the met69-to-lys substitution had no detectable abnormality at birth but did not begin walking until age 15 months and did so with an abnormal gait. Bilateral pes cavus was noted at age 6, and delayed nerve conduction velocity in the left ulnar nerve was measured at age 7. By age 18, she had severe lower limb weakness necessitating the use of a wheelchair and severe distal sensory loss in all 4 limbs. No other family member was known to be similarly affected. Electron microscopy of sural nerve biopsy demonstrated hypertrophy of the nerve with marked loss or abnormality of myelinated fibers.

The patient in whom Roa et al. (1993) demonstrated the ser72-to-leu substitution was an 8-year-old male who had severe hypotonia and weakness at birth, delayed motor milestones with normal speech development, and gradual improvement in motor abilities. He walked with the aid of leg braces and a walker at 7 years of age. There was marked distal atrophy of the lower limbs, mild weakness of the intrinsic hand muscles, and absent deep tendon reflexes in all 4 limbs. Sensory examination showed distal decrease in sensation to pinprick and temperature in all limbs. Motor nerve conduction velocity and sural nerve biopsy were typical of Dejerine-Sottas syndrome (145900). The mother of the patient, who died at 30 years of age from respiratory failure, had a history of similar neuromuscular problems. DNA was not available from that patient.

Ionasescu et al. (1996) found the same mutation in a patient with Dejerine-Sottas syndrome who also showed sensorineural hearing loss, nystagmus, and peripheral facial nerve weakness. The ser72l-to-leu mutation had occurred de novo. The authors stated that nystagmus and peripheral facial nerve weakness had not previously been reported in Dejerine-Sottas syndrome.

Marques et al. (1998) detected the same mutation in a 7-year-old girl with Dejerine-Sottas syndrome. The authors proposed that ser72 may be a hotspot for mutation.

Valentijn et al. (1995) identified a de novo mutation in the PMP22 gene of a patient with Dejerine-Sottas neuropathy (145900). Single-strand conformation analysis of PCR-amplified DNA fragments showed an additional fragment for exon 1 in the patient, which was absent in the unaffected parents. Sequence analysis showed a de novo C-to-A transversion at nucleotide 85 that resulted in an amino acid substitution his12-to-gln in the first transmembrane domain of PMP22. The patient had been described as case 13 by Ouvrier et al. (1987). At 4 years of age, the child's height and weight were below the third centile. There was generalized weakness of mild to moderate severity. All tendon reflexes were absent, except the triceps. Peripheral nerves were clinically enlarged. There was moderate truncal ataxia. Sensation was normal, except for mild loss of vibration sensation and diminished 2-point discrimination on the feet. Sensory action potentials could not be recorded from the right median or sural nerves. Motor nerve conduction velocity in the median nerve was 7 m/sec. Sural nerve biopsy at 2 years of age had shown reduced density of myelinated fibers, and all fibers were thinly myelinated and frequently surrounded by onion bulbs.