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2 muscular dystrophyFrom the Departments of Molecular Genetics and Biochemistry, Human Genetics, Pediatrics, and Neurology (Drs. Pegoraro, Stella, and Hoffman), University of Pittsburgh School of Medicine, Pittsburgh, PA; the Neurology Department (Drs. Marks and Scavina), A.I. duPont Institute, Wilmington, DE; the Department of Neurology (Dr. Garcia), Tulane University Medical Center, New Orleans, LA; the Department of Neurology (Dr. Crawford), John Hopkins University, Baltimore, MD; the Department of Neurology and Pediatrics (Dr. Mancias), University of Texas, Houston, TX; the Neurology Department (Dr. Connolly), Washington University in St. Louis, St. Louis, MO; the Regional Neuromuscular Center (Drs. Fanin, Martinello, Trevisan, and Angelini), University of Padova, Italy; the Neurology Department (Dr. Munk), The Toledo Hospital, Toledo, OH; Istituto di Neurologia (Dr. Servidei), Catholic University, Italy; Children's Hospital (Dr. Bönnemann), Harvard Medical School, Boston, MA; Department of Neurology (Dr. Bertorini), The University of Tennessee, Memphis, TN; Department of Pediatrics and Neurology (Dr. Acsadi), Wayne State University, Detroit, MI; The Center for Handicapped Children and Teenagers (Dr. Thompson), San Francisco, CA; Department of Pediatrics (Drs. Gagnon and Hoganson), University of Illinois, Chicago, IL; Department of Pediatrics (Dr. Carver), University of Miami, Miami, FL; and Department of Radiology (Dr. Zimmerman), Children's Hospital of Philadelphia, PA.
Address correspondence and reprint requests to Dr. Elena Pegoraro, the Department of Molecular Genetics and Biochemistry, Biomedical Science Tower W1211, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261.
Objective: To determine the number of primary laminin 
2 gene mutations and to conduct genotype/phenotype correlation in a cohort of laminin2-deficient congenital muscular dystrophy patients.
Background: Congenital muscular dystrophies (CMD) are a heterogenous group of muscle disorders characterized by early onset muscular dystrophy and a variable involvement of the CNS. Laminin 2 deficiency has been reported in about 40 to 50% of cases of the occidental, classic type of CMD.1,2 Laminin 2 is a muscle specific isoform of laminin localized to the basal lamina of muscle fibers, where it is thought to interact with myofiber membrane receptor, such as integrins, and possibly dystrophin-associated glycoproteins.3,4
Methods: Seventy-five CMD patients were tested for laminin 2 expression by immunofluorescence and immunoblot. The entire 10 kb laminin 2 coding sequence of 22 completely laminin 2-deficient patients was screened for causative mutations by reverse transcription (RT)-PCR/single strand conformational polymorphisms (SSCP) analysis and protein truncation test(PTT) analysis followed by automatic sequencing of patient cDNA. Clinical data from the laminin 2-deficient patients were collected.
Results: Thirty laminin 2-negative patients were identified (40% of CMD patients tested) and 22 of them were screened for laminin 2 mutations. Clinical features of laminin 2-deficient patients were similar, with severe floppiness at birth, delay in achievement of motor milestones, and MRI findings of white matter changes with normal intelligence. Loss-of-function mutations were identified in 95% (21/22) of the patients studied. SSCP analysis detected laminin 2 gene mutations in about 50% of the mutant chromosomes; PTT successfully identified 75% of the mutations. A two base pair deletion mutation at position 2,096-2,097 bp was present in 23% of the patients analyzed.
Conclusions: Our data suggest that the large majority of laminin 2-deficient patients show laminin 2 gene mutations.
Supported by a grant from the NIH (NINDS) R01 29525. Eric P. Hoffman is an Established Investigator of the American Heart Association.
Received December 26, 1997. Accepted in final form February 23, 1998.
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