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