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Published on: August 15, 2019
New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation
A Yanagisawa1, C Bouchet, P Y K Van den Bergh
1INSERM, U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Background:
Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance, often associated with CNS and ocular involvement. They are characterized by the abnormal glycosylation of alpha-dystroglycan, and caused by mutations in at least six genes encoding enzymes: FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE. POMT2 mutations have recently been identified in Walker-Warburg syndrome and in a milder muscle-eye-brain disease-like form.
Methods:
We studied mentally retarded patients with CMD, analyzed POMT2 by sequencing the coding regions, and also performed a haplotype analysis in all patients and their family members carrying the new POMT2 mutation.
Results:
We report three novel POMT2 mutations. One of these, p.Tyr666Cys, was homozygous in two unrelated patients and in a compound heterozygous state in others. All patients showed severe diffuse muscle weakness, microcephaly, severe mental retardation, and marked lordoscoliosis with hyperextended head. Elevated CK levels, cerebral cortical atrophy, and cerebellar vermis hypoplasia were constant findings. Mild cardiac abnormalities, focal white matter abnormalities, or partial corpus callosum hypoplasia were detected in single cases. Eye involvement was absent or mild. By genotype analysis, we defined a distinct 170kb haplotype encompassing POMT2 and shared by all the subjects harboring the mutation p.Tyr666Cys.
Conclusions:
Our results broaden the clinical spectrum associated with POMT2 mutations, which should be considered in patients with CMD associated with microcephaly, and severe mental retardation with or without ocular involvement.
Insights
New POMT2 gene mutations cause congenital muscular dystrophies (CMDs) with severe intellectual disability and microcephaly. These findings expand the known spectrum of dystroglycanopathies, aiding diagnosis in affected individuals.
Area of Science:
- Genetics
- Neurology
- Biochemistry
Background:
- Dystroglycanopathies are inherited muscle disorders characterized by abnormal alpha-dystroglycan glycosylation.
- Mutations in genes like POMT2 cause these conditions, often involving the central nervous system (CNS) and eyes.
Purpose of the Study:
- To investigate novel mutations in the POMT2 gene.
- To analyze the clinical and genetic characteristics of patients with POMT2 mutations.
Main Methods:
- Sequencing of POMT2 coding regions in patients with congenital muscular dystrophy (CMD) and intellectual disability.
- Haplotype analysis in patients and families with identified POMT2 mutations.
Main Results:
- Three novel POMT2 mutations were identified, including a recurrent p.Tyr666Cys mutation.
- Patients exhibited severe muscle weakness, microcephaly, profound intellectual disability, and spinal abnormalities.
- Consistent findings included elevated CK levels, cerebral cortical atrophy, and cerebellar hypoplasia; eye involvement was mild or absent.
Conclusions:
- POMT2 mutations present a broader clinical spectrum than previously recognized.
- These mutations should be considered in patients with CMD, microcephaly, and severe intellectual disability, with or without ocular symptoms.
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