Discovery:
Recessive Forms of OI

 

Recent discoveries expand our understanding of osteogenesis imperfecta (OI).

Genetics/Inheritance
Two recessive forms of OI were identified in 2006. Unlike the dominant forms of OI, the recessive forms do not involve mutations to the type I collagen genes. Instead, they involve two genes that affect collagen modification CRTAP (cartilage-associated protein) and LEPRE1, which produces prolyl 3-hydroxylase 1 (P3H1). These two proteins, CRTAP and P3H1, interact with collagen and modify amino acids in the collagen chains.
These discoveries provide important information for people diagnosed with severe OI based on clinical symptoms who do not carry a type I collagen mutation. Defects in CRTAP and P3H1 appear to account for most of the cases of severe/lethal OI which do have biochemically abnormal collagen, but do not have a collagen mutation. Recessive OI has been discovered only in individuals with lethal, severe or moderate OI. There is no evidence to date of a recessive form of mild OI.

When a child has recessive OI, there is a 25 percent chance per pregnancy that the parents will have another child with OI. Siblings of a person with a recessive form of OI have a 50 percent chance of being a carrier of the recessive gene.

The majority of cases of OI (possibly 85-90%) are caused by a dominant mutation in a gene coding for type I collagen (COL1A1 or COL1A2). These forms have recently been referred to as “Classical OI” in the research literature, and are described by the Sillence Classification of Type I through IV OI.

Types of Recessive OI
The information about recessive OI expands and enhances the list of types.

Type VI

  • Similar to Type IV classical OI in appearance and symptoms of OI
  • Distinguished by a characteristic mineralization defect seen in biopsied bone
  • Does not have a type I collagen mutation
  • Mode of inheritance is unknown but most likely recessive

Type VII

  • The first described cases resemble Type IV classical OI in many aspects of appearance and symptoms
  • In other instances the appearance and symptoms are similar to Type II lethal OI,
    except infants had white sclerae, small head and round face
  • Short humeri and femora
  • Short stature
  • Coxa vara is common (the acutely angled femur head affects the hip socket)
  • Results from recessive inheritance of a mutation to CRTAP gene. Partial function of CRTAP leads to moderate bone dysplasia while total absence of CRTAP has been lethal in all 4 identified cases

 Type VIII

  • Similar to Type II or Type III classical OI in appearance and symptoms except for white sclerae
  • Severe growth deficiency
  • Extreme skeletal under mineralization (DEXA L1-L4 = -6 to -7) 
  • Caused by absence/severe deficiency of P3H1 due to a mutation to the LEPRE1 gene

Impact of Discovery of Recessive Forms of OI

  • The majority of OI cases (possibly 85-90%) are still caused by a dominant mutation in one of the type I collagen genes
  • No specific treatment recommendations can be made for recessive OI at this time.
  • It is not clear that people with recessive OI will respond in the same way to the same treatments as people with dominant OI.
  • May provide specific information for families when a type I collagen mutation has not been found in the family member who has OI
  • Expands the information available to genetic counselors pertinent to the type of OI, prognosis, and odds of recurrence
  • Expands information available to genetic counselors regarding severely affected infants
  • Allows siblings of a person diagnosed with recessive OI to obtain testing to determine their carrier status
  • Allows for prenatal diagnosis in an affected family

Testing for Recessive OI
Testing information for recessive OI is available from Baylor College of Medicine, the National Institutes of Health and the Shriners Hospital for Children in Montreal. 

 Baylor Medical Genetics Laboratories
 Telephone: 1-800-411-4363
 Fax: 713-798-6584
 E-mail:
genetictest@bcm.edu
 Web site: www.bcm.edu/geneticlabs

OI Research Program at NICHD
 Telephone: 301-496-0741
 Fax: 301-480-3188
 E-mail:
oiprogram@mail.nih.gov
 Web site: http://www.oiprogram.nichd.nih.gov/

 Genetics Unit, Shriners Hospital for Children Canada
 Telephone: 514-843-7685
 Fax: 514-842-5587
 E-mail:
Glorieux@shriners.mcgill.ca
 Web site:  http://www.shriners-genetics.mcgill.ca/

References
Morello et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta, Cell; 127: 291-304. (October 20, 2006).

Barnes et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta, New England Journal of Medicine 2006; 355:2757-64. (December 28, 2006).

Cabral et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta, Nature Genetics 39: 359-365 (March 2007).

May 2007

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