and Molecular Genetics IV
November 16 (Friday), 2001
Required Reading: Principles
of Medical Genetics
TD, Collins FS, Ginsburg D
1998 Williams and Wilkins
Know basic structure of collagen:
- What is the critical amino acid sequence
- 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
bones with osteopenia
May also have
some joint laxity, short stature, and multiple deformities,
- What are the cardinal clinical manifestations
of classic EDS?
- 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
- 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 mothers eggs or fathers 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.