GENOTYPE–PHENOTYPE CORRELATIONS IN NONLETHAL OSTEOGENESIS IMPERFECTA CAUSED BY MUTATIONS IN THE HELICAL
DOMAIN OF COLLAGEN TYPE I
Frank Rauch, Liljana Lalic, Peter Roughley and Francis H Glorieux
Nur Rohmah12/338710/PMU/7375
Introduction
Osteogenesis Imperfecta
heritable connective
tissue disorder
mutation in COL1A1 or
COL1A2
Introduction
Introduction
Osteogenesis Imperfecta (OI)
Blue/grey sclera
Dentinogenesis imperfectabone fragility
Hearing loss
Introduction
Type I < IV < III < II
Type Clinical severity Typical features
I Mild non-deforming OI Normal height or mild short stature; blue sclera; no dentinogenesis imperfecta
II Perinatal lethal Multiple rib and long-bone fractures at birth; pronounced deformities; broad long bones, low density of skull bones on radiographs; dark sclera
III Severely deforming Very short; triangular face; severe scoliosis; greyish sclera; dentinogenesis imperfecta
IV Moderately deforming Moderately short; mild to moderate scoliosis; greyish or white sclera; dentinogenesis imperfecta
Objective
to investigated genotype–phenotype correlations in OI patients with glycine mutations in the triple helical domain of collagen type I.
Subject and method
Sample Patient Clinical characteristics
Total genomic DNA was
isolated from peripheral blood
Amplified by PCR and
sequencing
aligned with the GenBank reference
sequences
Statistical analysis
Subject and method
Sampel Patient
• 161 OI patients
DNA isolation
• Total genomic DNA was isolated from peripheral blood using the QIAamp DNA Blood Midi Kit
Collagen type I
mutation analysis
• All exons of the COL1A1 and COL1A2 genes amplified by PCR. The sequencing reactionusing a BigDye Terminator cycle sequencing kit . The nucleotide sequence was determined using an Applied Biosystems 3100 DNA sequencer.
Subject and method
Sequence traces were aligned with the GenBank reference sequencesCOL1A1 genomic DNA (AF017178) COL1A2 genomic DNA (AF004877.1), then compared and analyzed using BLAST.
Alignment
Statistical analysis
RESULTS AND DISCUSSION
RESULTS AND DISCUSSION
RESULTS AND DISCUSSION
Figure 1 Relationship between the triple helical position of glycine mutations in collagen type I a chains and the presence (+) or absence () of deformities or fractures at birth (DFB), blue sclera (BS), and dentinogenesis imperfecta (DI).
RESULTS AND DISCUSSION
Figure 2. Relationship between the positions of glycine substitutions in the triple helical domain of type I collagen and height z-scores
RESULTS AND DISCUSSION
Conclusion
• genotype–phenotype correlations for 161 OI patients with 111 distinct triple helical mutations of collagen type I
• Height correlated with the location of the mutation in the α2 chain but not in the α1.
• Patients with mutations affecting the first 120 amino acids at the amino-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta.
Manual Rumus Z-score :Z= X-M SDDimana: Z = Nilai standar
X = Rata-rata distribusiM = Nilai mentah yang akan dicari
nilai standarnyaSD = Standar deviasi distribusi
Rumus Z-score :
SDM-X Z