Major acquired and inherited connective tissue diseases

Question 1

What 2 features are expressed by a genetic connective tissue disease?

Answer 1

Functions of proteins expressed

Where involved proteins are expressed in the genome

Question 2

Why is therapy of connective tissue diseases usually guided by genotype instead of phenotypic effects, even though many conditions are defined by clinical features?

Answer 2

Phenotypic effects are highly variable and originate from a specific mutation, so it is easier to look at gene that has become mutated

Question 3

Are rarer forms of a connective tissue disease caused by the same gene as the common forms of that disease?

Answer 3

Rarer forms of connective tissue diseases can be caused by mutation of other genes as well as the characteristic gene mutations

Question 4

Give 2 benefits of molecular understanding of the genetic causes of connective tissue diseases?

Answer 4

Informs appropriate surveillance and prophylactic intervention

Question 5

What gene mutates to cause Marfan syndrome, and how many types of mutations are there?

Answer 5

FBN1/fibrillin-1 mutations produce defective elastic fibres, over 1800 different mutations (most missense) reported

Question 6

Give 8 examples of clinical features of Marfan syndrome?

Answer 6

Tall, long hands/feet and arm span that exceeds height, cardiovascular effects, high arched palate, long thin digits, upwards lens dislocation, myopia (near objects clear, far away blurry), hyperextensible joints

Question 7

How many types of mutations affect collagen fibres, and what determines which type of connective tissue is affected?

Answer 7

1000s of mutations that affect many different tissues, but impact depends on where gene mutation is expressed

Question 8

What are the most and least common mutations of genes that code for collagen fibres?

Answer 8

Most common mutations are single-base substitutions, less common are premature stop codon that causes haploinsufficiency

Question 9

What 2 gene mutations occur, and what effect do they have on collagen to cause Osteogenesis Imperfecta?

Answer 9

COL1A1 and COL1A2 mutations produce defective type 1 collagen fibres

Question 10

Why is Osteogenesis Imperfecta also called ‘brittle bone’ disease?

Answer 10

bone predominantly contains type 1 collagen fibres, but these are defective so the bone is more fragile in OI

Question 11

How do gene mutations usually change the structure of procollagen so that the type 1 collagen fibres are defective, in OI?

Answer 11

Common mutations cause glycine to be replaced with larger AA so that procollagen triple helix structure is loosely intertwined

Question 12

Are all OI cases caused by mutation of COL1A1 and COL1A2 genes?

Answer 12

No, some OI cases caused by mutation of other genes that regulate collagen assembly/function

Question 13

Describe the severity of type I Osteogenesis Imperfecta and the mutation that it is commonly caused by?

Answer 13

mildest, most common form that occurs when mutations cause quantitative defect/haploinsufficiency: half of normal amount of type 1 collagen produced

Question 14

Give 2 examples of clinical features of type I/mild OI?

Answer 14

Bones very fracture-prone

thin sclera allows blue choroid underneath to be seen

Question 15

Describe the severity of type II/perinatal lethal osteogenesis imperfecta, and the type of mutation that it is usually caused by?

Answer 15

most severe form that occurs when mutations cause qualitative defect resulting in abnormal type 1 collagen produced

Question 16

Give 5 clinical features of type II/perinatal lethal OI?

Answer 16

Very fragile bones cause intracranial fractures

severe breathing difficulties

severe osteopenia

skull osteomalacia

long bone and rib deformities

Question 17

What gene mutation causes skeletal development abnormalities, and explain this process in terms of how the collagen is affected?

Answer 17

COL2A1 mutations cause defective type 2 collagen production, which predominantly makes up cartilage that is replaced by bone in endochondral ossification, affecting skeletal development

Question 18

Give 6 clinical features of skeletal development abnormalities?

Answer 18

Short stature

enlarged joints

spinal curvature

early arthritis

cleft palate

vision and hearing defects

Question 19

Give 3 examples of conditions that can be caused by COL2A1 mutation expressing defective type 2 collagen and resulting in skeletal development abnormalities?

Answer 19

hypochondrogenesis, type 2 achondrogenesis, some stickler syndrome cases

Question 20

What 3 gene mutations cause Alport syndrome, what type of collagen is affected and where is this collagen predominantly found?

Answer 20

COL4A3, COL4A4, COL4A5 mutations cause defective type 4 collagen, which is a major component of basement membrane

Question 21

Give 3 clinical features of Alport syndrome?

Answer 21

CKD

Hearing loss

Eye abnormalities

Question 22

What is the incidence of Alport syndrome?

Answer 22

Incidence is 1 in 5000-10,000

Question 23

What gene mutation leads to the most common form of Alport syndrome, and what percentage of all cases does this form make up?

Answer 23

Most common form (85%) due to COL4A5 mutations

Question 24

Why is Alport syndrome a more severe disease in men than women?

Answer 24

X-linked disease, so men have more severe disease as they only have mutated gene copy, but women can be carriers

eg. renal failure more likely in men

Question 25

What types of gene mutations occur in Stickler syndrome, and what kind of collagen fibres do these affect?

Answer 25

Mutations in type IX/9 or type XI/11 collagen, which are essential for type 2 collagen fibre formation

Question 26

How many variants are there of the gene mutation that causes Stickler syndrome to be expressed?

Answer 26

There are at least 5 variants:
type I - COL2A1 mutations (75% of cases)
type II - COL11A1
type III - COL11A2 (non-ocular)
type IV - COL9A1 (recessive)
type V - COL9A2 (recessive)

Question 27

Give 4 clinical features of Stickler syndrome?

Answer 27

Causes flattened facial features

eye and ear problems

affected joints such as congenitally enlarged knees, wrists

cleft palate

Question 28

How many forms are there of Ehlers Danlos syndrome, and what gene mutations are they caused by?

Answer 28

At least 13 different forms, caused by mutation of one of at least 19 genes, including COL3A1, COL5A1, COL5A2 and the EDS forms present with overlapping symptoms and variable presentation

Question 29

Why can the correct form of Ehlers Danlos syndrome be difficult to diagnose based on clinical presentation only?

Answer 29

EDS forms present with overlapping symptoms and variable presentation

Question 30

What is the gene mutation that causes Type III/hypermobile EDS, what is the characteristic clinical feature and what is its incidence?

Answer 30

Caused by unknown gene defect

presents as benign hypermobility (very flexible joints)

incidence is 1 in 10,000-15,000

Question 31

What 2 gene mutations cause Type I/II/classic EDS, what are the 2 characteristic clinical features and what is its incidence?

Answer 31

Mutation of COL5A1/COL5A2 producing null allele, which is normally expressed in skin and other tissues that express type I collagen

presents as stretchy skin that scars and bruises easily, hypermobile joints

incidence is 1 in 20,000

Question 32

What gene mutation causes Type IV/vascular EDS, what are the 3 characteristic clinical features and what is its incidence?

Answer 32

Caused by COL3A1 mutations which are expressed in blood vessels and skin

presents as bruising, varicose veins, arterial rupture and organ rupture due to fragile skin and blood vessels

incidence in 1 in 200,000