Biochemical and Molecular Genetics IV

Collagen Disorders

Lecture 20

November 16 (Friday), 2001

Required Reading: Principles of Medical Genetics

Gelerhter TD, Collins FS, Ginsburg D

1998 Williams and Wilkins

Pages: 143-151

Know basic structure of collagen:

    • What is the critical amino acid sequence pattern?
    • Understand the process of collagen formation from the polypeptide chains through procollagen molecules to mature collagens.

    • Know the triple helical structure of collagen and its precursor lesions and know that mutations at various points in collagen synthesis, processing and secretion can cause disease. Understand that there are many different types of collagen that have different levels of tissue expression and that are involved in different diseases.

  • Know that some types of collagen are heterotrimers (eg Type I collagen) and others are homotrimers (eg. Type III collagen). What is the difference?

Understand that there are different types of collagen, some that are more prevalent in some tissues and less prevalent in others.

    • You should understand how the expression pattern and localization of different types of collagens in different tissues is associated with different clinical manifestations of connective tissue disorders (eg. if type I collagen is not a major collagen in the vascular system, you would not anticipate major vascular problems with genetic alterations causing abnormal type I collagen).

    • Where is type I collagen predominantly located? Type III?
    • What disorders are associated with type I collagen defects?
    • Why might one type of mutation affecting type I collagen result in a relatively mild form of OI while a different type of alteration may cause a severe, neonatal lethal form of OI?
    • Why are defects in type III collagen associated with such significant morbidity d mortality? What disease is caused by defects in type III collagen and what are features of this condition?

Know the different kinds of mutations that may occur to cause disease and be able to describe the predicted consequences of certain kinds of mutations:

    • Understand how different types of mutations in genes encoding structural collagen proteins may cause different kinds or severity of disease.

    • Be able to recognize and understand the concept of "protein suicide" and also understand why a ‘null’ allele for an autosomal dominant disorder may have less of a devastating phenotypic effect than a point mutation that causes protein suicide. Understand the differences between mutations that cause qualitative defects in the collagen produced versus those that cause quantitative defects.

Know the general types of and wide variety of symptoms that are seen in the Ehlers-Danlos and Osteogenesis Imperfecta syndromes.

    • What are the cardinal clinical manifestations of OI?

Brittle bones with osteopenia

Blue sclerae +/-

Dentinogenesis imperfecta +/-

May also have some joint laxity, short stature, and multiple deformities, easy bruising

    • What are the cardinal clinical manifestations of classic EDS?

Joint hyperextensibility and dislocations

Abnormal "tissue paper" scars

Easy bruising

Increased elasticity of skin

    • You do not (yet) need to know all of the specific details about each of the symptoms of the various subtypes of each of these syndromes, but as noted above, you should know classic features of OI and EDS and should realize that there are different types of OI and different types of EDS. You should also know the general features of the specific type of OI (OI type II) and the specific type of EDS (EDS type IV also known as the "vascular type" of EDS) that are associated with significantly increased morbidity and mortality.
    • You should know when to suspect one of these conditions based on physical findings. You should have some sense about the general approach to further evaluation of these individuals.
    • You should be able to distinguish classic OI phenotypes from EDS phenotypes. Specifically, you should be able to compare and contrast the classic features and pathophysiology of OI and EDS. How are the disorders the same? Is there overlap? How are they different?
    • Understand that the inheritance pattern of many connective tissue disorders is autosomal dominant, but other inheritance patterns have also been described.
    • Understand genetic counseling issues in connective tissue disorders especially regarding recurrence risks. Know that if a severely affected child is born to healthy, unaffected parents, one must consider the possibility of a new mutation, autosomal recessive inheritance AND gonadal or germline mosaicism of an autosomal dominant disorder. This means that a certain percentage of either the mother’s eggs or father’s sperm contains this mutation. This has been described in several cases of severe Osteogenesis Imperfecta (OI type II). Thus, a couple would be at an increased risk of having another child with the same autosomal dominant disorder even though they themselves do not have the disorder. This is an important concept in genetics that was not discussed in the textbook, but will be discussed in lecture.