title: Clinical and molecular study in congenital muscular dystrophy with partial laminin alpha 2 (LAMA2) deficiency.
abstract: Complete laminin alpha2 (LAMA2) deficiency causes approximately half of congenital muscular dystrophy (CMD) cases. Many loss-of-function mutations have been reported in these severe, neonatal-onset patients, but only single missense mutations have been found in milder CMD with partial laminin alpha2 deficiency. Here, we studied nine patients diagnosed with CMD who showed abnormal white-matter signal at brain MRI and partial deficiency of laminin alpha2 on immunofluorescence of muscle biopsy. We screened the entire 9.5 kb laminin alpha2 mRNA from patient muscle biopsy by direct capillary automated sequencing, single strand conformational polymorphism (SSCP), or denaturing high performance liquid chromatography (DHPLC) of overlapping RT-PCR products followed by direct sequencing of heteroduplexes. We identified laminin alpha2 sequence changes in six of nine CMD patients. Each of the gene changes identified, except one, was novel, including three missense changes and two splice-site mutations. The finding of partial laminin alpha2 deficiency by immunostaining is not specific for laminin alpha2 gene mutation carriers, with only two patients (22%) showing clear causative mutations, and an additional three patients (33%) showing possible mutations. The clinical presentation and disease progression was homogeneous in the laminin alpha2-mutation positive and negative CMD patients.
authors.affiliation: Research Center for Genetic Medicine, Children's Research Hospital, Washington, DC, USA.
authors.forename: Zivana
authors.initials: Z
authors.lastname: Tezak
authors.forename: Paola
authors.initials: P
authors.lastname: Prandini
authors.forename: Marco
authors.initials: M
authors.lastname: Boscaro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marin
authors.forename: Joseph
authors.initials: J
authors.lastname: Devaney
authors.forename: Michael
authors.initials: M
authors.lastname: Marino
authors.forename: Marina
authors.initials: M
authors.lastname: Fanin
authors.forename: Carlo P
authors.initials: CP
authors.lastname: Trevisan
authors.forename: Julie
authors.initials: J
authors.lastname: Park
authors.forename: Weslie
authors.initials: W
authors.lastname: Tyson
authors.forename: R
authors.initials: R
authors.lastname: Finkel
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
mesh_terms: D003025:Clubfoot / Q000209:etiology / Q000235:genetics; D002658:Developmental Disabilities / Q000209:etiology / Q000235:genetics; D005183:Failure to Thrive / Q000209:etiology / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007797:Laminin / Q000032:analysis / Q000235:genetics*; D008297:Male; D019957:Motor Skills Disorders / Q000209:etiology / Q000235:genetics; D009123:Muscle Hypotonia / Q000209:etiology / Q000235:genetics; D009132:Muscles / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000150:complications / Q000151:congenital / Q000175:diagnosis* / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009692:Nucleic Acid Heteroduplexes / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: D007797:Laminin; D009692:Nucleic Acid Heteroduplexes; D022821:RNA Splice Sites; C102645:laminin alpha 2