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Genetic Testing

Rehabilitation

Osteogenesis imperfecta (OI) is a spectrum of genetic disorders with decreased bone density and increased bone fragility.

Most of the cases of OI are inherited in autosomal dominant fashion with mutations in COL1A1 or COL1A2 genes.

Several autosomal recessive genes which usually encode proteins responsible for posttranslational modifications, assembly of triple helix, chaperoning of the type I pro collagen heterotrimer and bone homeostasis are getting identified in remaining cases of OI

In patients from consanguineous families, other than COL1A1 and COL1A2, twelve genes have been reported for OI.


Autosomal Mutation

OI IS A HERITABLE CONNECTIVE TISSUE DISORDER CAUSED BY DOMINANT MUTATION IN THE COL1A1 OR COL1A2 GENES THAT ENCODE FOR TYPE 1 COLLAGEN

EITHER CHILDREN HAVE LESS COLLAGEN OR A POOR QUALITY COLLAGEN

LESS THAN 10% OF OI CASES ARE CAUSED BY RECESSIVE MUTATION IN OTHER GENES IN THE COLLAGEN PATHWAY

Fewer than 10 percent of OI cases are believed to be caused by recessive mutations in other genes in the collagen pathway. Mutations in the genes for prolyl 3-hydroxylase (LEPRE1) and for cartilage - associated protein (CRTAP) have been identified.


Biochemical pathway of Collagen Type 1 formation


Nucleus: 90% are heterozygous for COLA1 or COLA2 gene mutation

Pro-Collagen enter lumen of ER and 2 α1 and I α2 chains align forms triple helix helped by disuphide bonds and hydroxylation

CRTAP, LEPRE1 and PPIB genes, is responsible for the 3-hydroxylation of P986

FKBP10 also acts as a molecular chaperone for type I (pro)collagen. The protein product of PLOD2 hydroxylates telopeptide lysines in the RER. HSP47 encoded by SERPINH1 is thought to maintain the stability of the triple helix

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Biochemical pathway of Collagen Type 1 formation


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Classifications


  • 1906 - Looser ( looser zone seen in osteomalacia) made first attempt and classified OI into congenital and tarda.

  • 1950-70s Bone Metabolism: Urist et al

  • 1979 – Sillence proposed a numerical classification based on clinical features and genetic findings ( RCH – Australia) and classified OI into 4 types.

  • 1984 – Sillence subdivided Type II into A, B, C based on radiographic features


New Genes in Bone Development: What's New in Osteogenesis Imperfecta


J Clin Endocrinol Metab. 2013 Aug

Joan Marini: Bone and ECM (extracellular matrix) Division

PARADIGM SHIFT IN UNDERSTANDING OF OI AS A PURE COLLAGEN DISORDER

A number of noncollagenous genes whose protein products interact with collagen have been identified as the cause(s) of rare forms of OI


Classical OI (Type I – IV) AD


  • Type I : Mild non-deforming , triad of fracture, blue sclera and hearing loss

  • Type II : Perinatal, lethal form

  • Type III : Progressively deforming, non-lethal form, multiple fractures, grey/blue sclerae, dentinogenesis imperfect, popcorn calcification in distal femur

  • Type IV : broad range of phenotypes, frequent long bone fractures, normal dentine, achieve ambulation

Non-Classical OI (Type V-XII)


  • Type V: AD, calcification of interosseous memb, radiodense metaphyseal bands of growth plate, tendency for hyperplastic callus.

  • Defect in protein coding for IFTIM5 (Interferon induced transmembrane protein 5) Or BRIL ( Bone Restricted IFTIM like Protein)


Autosomal Recessive OI


  • Type VI: Mineralization defect, SERPINF1 involved – Serine pathway which encodes PEDF which helps in bone angiogenesis

  • Se PEDF level are absent

  • Iliac crest biopsy, fish scale pattern of lamellar bone.


Collagen 3 hydroxylation defect


  • Type VII, VIII, IX OI

  • CRTAP, LEPRE1, PPIB

  • Type X and XI OI (SERPINH and FKPB 10)

  • Collagen Chaperones defects

  • Type XII OI: BMP 1 defect ( C propeptide cleavage enzyme defect)

  • Unknown OI types



Publications

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