Clinical and Molecular Characterization
of Collagen VI Myopathies
Russell Butterfield MD/PhD
University of Utah
Departments of Neurology and Pediatrics
August 15, 2010
Collagen VI myopathies
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Bethlem Myopathy
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Proximal muscle weakness and atrophy
Dynamic contractures in distal joints (fingers, wrists, elbows, and
ankles)
Onset in first or second decade
Slowly progressive in adult years
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Ullrich Congenital Muscular Dystrophy

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2/3 of patients >50 years-old require assistance for ambulation
Severe weakness/hypotonia in early infancy
Proximal joint contractures
Distal joint hyperlaxity
Collagen VI myopathies likely represent spectrum of
phenotypes defined by type and distribution of
contractures
Three genes of Collagen VI
N1
TH
C1
C2
a1(VI)
C
a2(VI)
•C
N10 N9
N8
N7
N6
N5
N4 N3 N2
N1
TH
C1
C2 C3 C4 C5
a3(VI)
C
von Willebrand factor A domain
Alternatively spliced vWF A
Triple-helix
Lysine/proline repeats
Fibronectin type III motif
Kunitz protease inhibitor motif
COL6A1- 4246 base pairs

gctctcactctggctgggagcagaaggcagcctcggtctctgggcggcggcggcggccca ctctgccctggccgcgctgtgtggtgaccgcaggccccagacatgagggcggcccgtgct
ctgctgcccctgctgctgcaggcctgctggacagccgcgcaggatgagccggagaccccg agggccgtggccttccaggactgccccgtggacctgttctttgtgctggacacctctgag
agcgtggccctgaggctgaagccctacggggccctcgtggacaaagtcaagtccttcacc aagcgcttcatcgacaacctgagggacaggtactaccgctgtgaccgaaacctggtgtgg
aacgcaggcgcgctgcactacagtgacgaggtggagatcatccaaggcctcacgcgcatg cctggcggccgcgacgcactcaaaagcagcgtggacgcggtcaagtactttgggaagggc
acctacaccgactgcgctatcaagaaggggctggagcagctcctcgtggggggctcccac ctgaaggagaataagtacctgattgtggtgaccgacgggcaccccctggagggctacaag
gaaccctgtggggggctggaggatgctgtgaacgaggccaagcacctgggcgtcaaagtc ttctcggtggccatcacacccgaccacctggagccgcgtctgagcatcatcgccacggac
cacacgtaccggcgcaacttcacggcggctgactggggccagagccgcgacgcagaggag gccatcagccagaccatcgacaccatcgtggacatgatcaaaaataacgtggagcaagtg
tgctgctccttcgaatgccagcctgcaagaggacctccggggctccggggcgaccccggc tttgagggagaacgaggcaagccggggctcccaggagagaagggagaagccggagatcct
ggaagacccggggacctcggacctgttgggtaccagggaatgaagggagaaaaagggagc cgtggggagaagggctccaggggacccaagggctacaagggagagaagggcaagcgtggc
atcgacggggtggacggcgtgaagggggagatggggtacccaggcctgccaggctgcaag ggctcgcccgggtttgacggcattcaaggaccccctggccccaagggagaccccggtgcc
tttggactgaaaggagaaaagggcgagcctggagctgacggggaggcggggagaccaggg agctcgggaccatctggagacgagggccagccgggagagcctgggccccccggagagaaa
ggagaggcgggcgacgaggggaacccaggacctgacggtgcccccggggagcggggtggc cctggagagagaggaccacgggggaccccaggcacgcggggaccaagaggagaccctggt
gaagctggcccgcagggtgatcagggaagagaaggccccgttggtgtccctggagacccg ggcgaggctggccctatcggacctaaaggctaccgaggcgatgagggtcccccagggtcc
gagggtgccagaggagccccaggacctgccggaccccctggagacccggggctgatgggt gaaaggggagaagacggccccgctggaaatggcaccgagggcttccccggcttccccggg
tatccgggcaacaggggcgctcccgggataaacggcacgaagggctaccccggcctcaag ggggacgagggagaagccggggaccccggagacgataacaacgacattgcaccccgagga
gtcaaaggagcaaaggggtaccggggtcccgagggcccccagggacccccaggacaccaa ggaccgcctgggccggacgaatgcgagattttggacatcatcatgaaaatgtgctcttgc
tgtgaatgcaagtgcggccccatcgacctcctgttcgtgctggacagctcagagagcatt ggcctgcagaacttcgagattgccaaggacttcgtcgtcaaggtcatcgaccggctgagc
cgggacgagctggtcaagttcgagccagggcagtcgtacgcgggtgtggtgcagtacagc cacagccagatgcaggagcacgtgagcctgcgcagccccagcatccggaacgtgcaggag
ctcaaggaagccatcaagagcctgcagtggatggcgggcggcaccttcacgggggaggcc ctgcagtacacgcgggaccagctgctgccgcccagcccgaacaaccgcatcgccctggtc
atcactgacgggcgctcagacactcagagggacaccacaccgctcaacgtgctctgcagc cccggcatccaggtggtctccgtgggcatcaaagacgtgtttgacttcatcccaggctca
gaccagctcaatgtcatttcttgccaaggcctggcaccatcccagggccggcccggcctc tcgctggtcaaggagaactatgcagagctgctggaggatgccttcctgaagaatgtcacc
gcccagatctgcatagacaagaagtgtccagattacacctgccccatcacgttctcctcc ccggctgacatcaccatcctgctggacggctccgccagcgtgggcagccacaactttgac
accaccaagcgcttcgccaagcgcctggccgagcgcttcctcacagcgggcaggacggac cccgcccacgacgtgcgggtggcggtggtgcagtacagcggcacgggccagcagcgccca
gagcgggcgtcgctgcagttcctgcagaactacacggccctggccagtgccgtcgatgcc atggactttatcaacgacgccaccgacgtcaacgatgccctgggctatgtgacccgcttc
taccgcgaggcctcgtccggcgctgccaagaagaggctgctgctcttctcagatggcaac tcgcagggcgccacgcccgctgccatcgagaaggccgtgcaggaagcccagcgggcaggc
atcgagatcttcgtggtggtcgtgggccgccaggtgaatgagccccacatccgcgtcctg gtcaccggcaagacggccgagtacgacgtggcctacggcgagagccacctgttccgtgtc
cccagctaccaggccctgctccgcggtgtcttccaccagacagtctccaggaaggtggcg ctgggctagcccaccctgcacgccggcaccaaaccctgtcctcccacccctccccactca
tcactaaacagagtaaaatgtgatgcgaattttcccgaccaacctgattcgctagatttt ttttaaggaaaagcttggaaagccaggacacaacgctgctgcctgctttgtgcagggtcc
tccggggctcagccctgagttggcatcacctgcgcagggccctctggggctcagccctga gctagtgtcacctgcacagggccctctgaggctcagccctgagctggcgtcacctgtgca
gggccctctggggctcagccctgagctggcctcacctgggttccccaccccgggctctcc tgccctgccctcctgcccgccctccctcctgcctgcgcagctccttccctaggcacctct
gtgctgcatcccaccagcctgagcaagacgccctctcggggcctgtgccgcactagcctc cctctcctctgtccccatagctggtttttcccaccaatcctcacctaacagttactttac
aattaaactcaaagcaagctcttctcctcagcttggggcagccattggcctctgtctcgt tttgggaaaccaaggtcaggaggccgttgcagacataaatctcggcgactcggccccgtc
tcctgagggtcctgctggtgaccggcctggaccttggccctacagccctggaggccgctg ctgaccagcactgaccccgacctcagagagtactcgcaggggcgctggctgcactcaaga
ccctcgagattaacggtgctaaccccgtctgctcctccctcccgcagagactggggcctg gactggacatgagagccccttggtgccacagagggctgtgtcttactagaaacaacgcaa
acctctccttcctcagaatagtgatgtgttcgacgttttatcaaaggccccctttctatg ttcatgttagttttgctccttctgtgtttttttctgaaccatatccatgttgctgacttt
tccaaataaaggttttcactcctctaaaaaaaaaaaaaaaaaaaaa
Where are we now in collagen VI myopathies?
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Collagen VI disorders are increasingly recognized
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Clinical spectrum expanding
Progression/prognosis are not well defined
No specific treatments
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Likely among the most common muscular
dystrophies/myopathies
Treatments in development based on correction of abnormal
mitochondrial function
Outcome measures for potential clinical studies are not
well defined
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How do we measure success of a particular therapy?
Where are we in genetics of Collagen VI
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Dominant and recessive inheritance has been described
for both BM and UCMD
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Most mutations identified are specific to a single
person/family
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Variant vs. mutation is often unclear
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Consistent genotype/phenotype correlations lacking
Collagen VI at the University of Utah
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CLIA certified genetic testing has been available at the
Utah Genome Center since 2006
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To date, testing has been completed almost 400 patients.
Since patient samples are sent without clinical data we do not
know the clinical history of these patients
Natural history and genotype/phenotype project
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Re-contacting all patients who have had genetic testing for
collagen VI to collect detailed clinical data allowing correlation
with the genotype data already obtained.
United Dystrophinopathy Project
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Multi-centered natural history and genotype/phenotype
study
Now >1000 participants from 7 participating centers
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Children's Hospital of Philadelphia, Philadelphia, PA
University of Minnesota, Minneapolis, MN
Nationwide Children's Hospital, Columbus, OH
University of Iowa, Iowa City, Iowa
University of Utah, Salt Lake City, UT
Washington University, St. Louis, MO
University of California, Davis, Sacramento, California
Patients are seen on yearly basis
Confirmation of genetic diagnosis
390
clinical samples
genotyped
86
Parent/sib
carrier testing
39
positive
47
negative
304
Full sequencing
of COL6A1,2,3
141
patients with
no mutation
detected
163
patients with
variant
detected
Of 163 with variant detected: 91 probably pathogenic, 72 unknown significance
Muscle
Patient
Genes
COL6A
Collagen VI myopathy study at Utah

Catalog detailed clinical and genetic data in patients with Collagen VI
myopathies
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Clarify breadth of potential phenotypes
Detail natural history (progression over time)
Improve accuracy of genetic diagnosis and prognosis
Define genotype/phenotype relationships
Stimulate development of potential therapies
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Provide a resource for investigators conducting clinical trials
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Well defined cohorts
Appropriate outcome measures
Improved understanding of molecular pathogenesis
Facilitate collaboration among investigators, families, and others
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Integration with CMDIR
Establishment of collaborations leaders in the field
Patient Recruitment
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Primary recruitment from Utah Genome Center since Jan
2010
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Goal is to re-contact patients for whom we have
completed sequencing to collect clinical data
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Over 400 patients with genetic testing since 2006 with 50
enrolled thus far
Primary contact is through referring physician
Anticipated expansion of enrollment to include any
patient with collagen VI myopathy diagnosis
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Summer 2010
Enrollment/Participation
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All patients with collagen VI myopathy phenotypes (ie.
Bethlem myopathy or Ullrich CMD) are eligible to enroll
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A clinic visit is not required for participation
Participants will fill out a short questionnaire detailing
symptoms and physical findings
We will request records from treating physicians including
results of genetic testing (if done outside UGC) and other
diagnostic tests
In some cases, we may request a sample from skin or muscle
biopsy if they are already in existence
A couple areas of interest in our lab
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Mutation negative collagen VI patients
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46% patients with no identifiable mutation
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Potential explanations:
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Deletion mutation not identifiable by sequencing from genomic DNA
Mutation in non-coding regulatory region
Allelic locus or secondary collagen VI defect
Non-collagen VI disorder
Defining pathogenicity (or non-pathogenicity) “variants”
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Some of these with decreased collagen VI on muscle or skin biopsy
163/304 samples with sequencing of all 3 COL6A genes
identified variant
72 of these (44%) are of uncertain pathogenicity
High throughput genomics—transcriptome, exome
sequencing
Acknowledgements
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Utah Genome Center,
Robert Weiss, Director

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Kathryn Swoboda
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Weiss lab: Diane Dunn, Brett
Duval
Swoboda group: Lahdan
Heidarian
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Funding:
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Muscular Dystrophy Association
NIH-Loan Repayment Program
Primary Children’ Foundation,
CHRC
Collaborators
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Kevin Flanigan-Nationwide
Children’s
Carsten Bönnemann-CHOP
Thank you to CureCMD for the opportunity to participate in this conference.