title: POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental retardation.
abstract: BACKGROUND
  Alpha-dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance characterized by abnormal glycosylation of alpha-dystroglycan. Although six genetic causes have been identified (FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE) many alpha-dystroglycanopathy patients remain without a genetic diagnosis after standard exon sequencing. To date POMT2 mutations have been identified in CMD cases with a wide range of clinical severities from Walker-Warburg syndrome to limb girdle muscular dystrophy without structural brain or ocular involvement.
  
  
  METHODS
  We analyzed POMT2 in six CMD patients, who had severe diffuse muscle weakness, generalized joint contractures, microcephaly, severe mental retardation and elevated CK levels. Eye involvement was absent or limited to myopia or strabismus. We sequenced the coding regions of POMT2 using genomic DNA and cDNA generated from blood lymphocytes or B lymphoblastoid cell lines. Quantitative PCR analysis of genomic DNA was used to identify and determine the breakpoints of large deletions.
  
  
  RESULTS
  We report five novel mutations in POMT2, four of which were outside of coding exons, two large genomic deletions and two intronic single base substitutions that induced aberrant mRNA splicing.
  
  
  CONCLUSIONS
  Large scale DNA rearrangements (such as large deletions) and cryptic splice mutations, that can be missed on standard sequencing of genomic DNA, may be relatively common in POMT2. Additional techniques, such as sequencing of cDNA are needed to identify all mutations. These results also confirm that POMT2 mutations are an important cause of the less severe alpha-dystroglycanopathy phenotypes.
authors.affiliation: Inserm, U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, UPMC University Paris 06, UMR_S582, IFR14, Paris, France.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yanagisawa
authors.forename: Céline
authors.initials: C
authors.lastname: Bouchet
authors.forename: Susana
authors.initials: S
authors.lastname: Quijano-Roy
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vuillaumier-Barrot
authors.forename: Nigel
authors.initials: N
authors.lastname: Clarke
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: Makiko
authors.initials: M
authors.lastname: Osawa
authors.forename: Tamao
authors.initials: T
authors.lastname: Endo
authors.forename: Ana Lia
authors.initials: AL
authors.lastname: Taratuto
authors.forename: Nathalie
authors.initials: N
authors.lastname: Seta
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
mesh_terms: D000293:Adolescent; D000483:Alleles; D001483:Base Sequence; D002675:Child, Preschool; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004252:DNA Mutational Analysis; D018076:DNA, Complementary; D049030:Dystroglycans / Q000378:metabolism; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics* / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics; D012326:RNA Splicing; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D018076:DNA, Complementary; D049030:Dystroglycans; D004247:DNA; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase