CMT4B2 and Early Onset Glaucoma Research - from France

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Abstract from the American Journal of Human Genetics 2003 Apr 8;72(5)

Mutations in MTMR13, a New Pseudophosphatase Homologue of MTMR2 and

Sbf1, in Two Families with an Autosomal Recessive Demyelinating Form of

Charcot-Marie-Tooth Disease Associated with Early-Onset Glaucoma.

Azzedine H, Bolino A, Taieb T, Birouk N, Di Duca M, Bouhouche A, Benamou

S, Mrabet A, Hammadouche T, Chkili T, Gouider R, Ravazzolo R, Brice A,

Laporte J, LeGuern E.

U289 INSERM, Groupe Hospitalier Pitie-Salpetriere, Paris, France.

Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR)

inheritance is a heterogeneous group of inherited motor and sensory

neuropathies. In some families from Japan and Brazil, a demyelinating

CMT, mainly characterized by the presence of myelin

outfoldings on nerve biopsies, cosegregated as an autosomal recessive

trait with

early-onset glaucoma. We identified two such large consanguineous

families from

Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We

mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping

the locus for an isolated

demyelinating ARCMT (CMT4B2). In these two families, we identified two

different nonsense mutations in the myotubularin-related 13 gene,

MTMR13.

The MTMR protein family includes proteins with a phosphoinositide

phosphatase activity, as well as proteins in which key catalytic

residues are missing and that are thus called " pseudophosphatases. "

MTM1, the first identified member of this family, and MTMR2 are

responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth

disease type 4B1, an isolated peripheral neuropathy with myelin

outfoldings, respectively. Both encode active phosphatases.

It is striking to note that mutations in MTMR13 also cause peripheral

neuropathy with myelin outfoldings, although it belongs to a

pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1.

This is the first human disease caused by mutation in a

pseudophosphatase, emphasizing the important function of these

putatively inactive enzymes. MTMR13 may be important for the

development of both the peripheral nerves and the trabeculum meshwork,

which permits the outflow of the aqueous humor. Both of these tissues

have the same embryonic origin.