PMP22 and Myelin

[Guest guest]

PMP22 and Myelin

ANN Poster Session Seattle Tuesday, April 28, 2009 4:00 PM

[s15.002] Clinical and Schwann Cell Phenotypes in a Patient with PMP22

Homozygous Null Mutation

Istvan K. Katona, A. Saporta, Louise Carr, Fiona Macdonald, Louise

Brueton, Ueli Suter, E. Shy, M. Reilly, Jun Li, Helen P. Roper,

Zurich, Switzerland, London, United Kingdom, Detroit, MI, Birmingham, United

Kingdom

OBJECTIVE: To determine the molecular function of PMP22 in human peripheral

myelin by evaluating clinically, physiologically and morphologically a patient

with a homozygous deletion of chromosome 17p11.2

BACKGROUND: PMP22 is a structural protein of the peripheral myelin with unknown

function. Heterozygous deletion of chromosome 17p11.2, containing PMP22, causes

hereditary neuropathy with liability to pressure palsies (HNPP). While important

information has been learned from patients with HNPP, biological functions of

PMP22 in humans are largely unexplored due to the rarity of patients with PMP22

null mutation.

DESIGN/METHODS: A 7 year old boy with a homozygous deletion of chromosome

17p11.2 was evaluated clinically, by neurophysiology, and by punch skin biopsy.

RESULTS: At 4 months of age the patient was described as a floppy infant. Motor

milestones were delayed. At seven years of age, weakness was only mild in

intrinsic hand muscles. In contrast, large fiber sensory modalities were

profoundly abnormal and the patient required a frame due to sensory ataxia.

Nerve conduction velocities were slow. A glabrous skin biopsy revealed onion

bulb -like structures in the dermal nerves. Striking redundant basal lamina from

Schwann cells was observed within the onion bulbs. A similar redundancy of basal

lamina was seen in homozygous pmp22 null-mice where they were hypothesized to

result from a loss of interaction between Pmp22 and 6 4-integrin.

Immunohystochemistry with MBP antibody shows many Schwann cells lining up along

axons, but failing to form mature internodes, suggesting impaired or incomplete

differentiation of myelinating Schwann cells.

CONCLUSIONS/RELEVANCE: Our results demonstrate that PMP22 is necessary for basal

lamina organization and the maturation of myelinating Schwann cells. Without

PMP22 Schwann cells cannot form mature myelinated internodes. These results

suggest that myelinating Schwann cells without PMP22 are arrested at an immature

stage, which we are working to characterize. The reasons for the predominant

sensory phenotype of our patient are unclear.

Supported by: This study is supported by the Muscular Dystrophy Association and

the NIH.