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Genetics Flashcards

1
Q

What musculoskeletal disorder is a growth factor receptor defect?

A

Achondroplasia

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2
Q

What musculoskeletal disorders are collagen and connective tissue disorders?

A

Osteogenesis imperfecta, Ehlers-Danlos syndrome, Marfan syndrome

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3
Q

What is achondroplasia also known as? How is it inherited genetically?

A

Dwarfism. Autosomal dominant

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4
Q

What’s the avg height for men and women w/ achondroplasia?

A

4’4” and 4’1”

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5
Q

What is the easiest clinical sign of achondroplasia?

A

disproportionately short arms and legs

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6
Q

What does achondroplasia literally mean in Greek?

A

w/o cartilage formation

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7
Q

What’s the oldest known birth defect?

A

achondroplasia

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8
Q

what are the hallmark signs at birth for achondroplasia?

A

frontal bossing (prominent forehead), midface hypoplasia (underdeveloped midface), short limbs and long narrow trunk

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9
Q

How often does achondroplasia occur? What are their alleles like?

A

1:20,000. All affected individuals are heterozygote (Aa), fatal as homozygote

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10
Q

What is the mutation in that causes achondroplasia? What does this mutation do? What effect does FGFR3 have on bone growth?
What does the mutated FGFR3 receptor do?

A

Mutation in Fibroblastic Growth Factor Receptor-3 (FGFR3).
This mutation limits process of ossification (formation of bone from cartilage)
FGFR3 known to have negative regulatory effect on bone growth.
Mutated FGFR3 receptor is constitutively active (so leads to shortened bones.

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11
Q

How much penetrance do we see in achondroplasia?

A

100%

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12
Q

How many cases of achondroplasia are inherited from parents? how many cases are de novo mutations (mutation in germ cells)? are most de novo cases from maternal or paternal?

A

less than 20%.
greater than 80%.
Paternal (usually advanced paternal age)

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13
Q

What is Fibroblast growth factor receptor (FGFR3)? How is it activated?
Where is it expressed in high levels?

A

transmembrane bound tyrosine kinase.
Activated by ligand-induced dimerization of the receptor.
expressed in high levels in pre-bone cartilage.

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14
Q

What effect does FGFR3 have on bone growth (in achondroplasia)?
What mutation leads to mutated FGFR3 receptor? What percentage of the cases of achondroplasia have this mutation?

A

Negative regulatory effect, so mutation would likely have consequences in bone growth.
Mutation= G1138A nucleotide change, which leads to change in the amino acid at that position (G380R).
98%

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15
Q

In achondroplasia, where is the G1138A nucleotide (G380R amino acid) mutation located, and what does it do?

A

transmembrane domain of protein, introduces charged amino acid into hydrophobic domain of receptor and causes dimerization, which results in constitutive activation (ligand-independent). This decreases ossification.

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16
Q

In achondroplasia, what does the G1138A mutation do?

A

introduces a new restriction enzyme site in FGFR3 gene, called Sfc1. When it’s amplified by PCR and cut with Sfc1, you can determine heterozygosity and homozygosity for the mutation.

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17
Q

what is acanthosis nigricans?

A

dark, thick, velvety skin in body folds and creases. seen in severe achondroplasia with developmental delay and acanthuses nigricans (SADDAN)

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18
Q

Give an achondroplasia summary

A

Autosomal dominant dwarfism, mutation in FGFR3 gene, common mutation is at G1138A. To diagnose genetically: introduction of Scf1 site from mutation, we can detect affected heterozygotes vs normal individuals.

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19
Q

tell about collagen in the body

A

most abundant protein in the body, 20% of protein mass. in bones and cartilage constitutes 60% of protein.

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20
Q

how many genes are there for collagen?
How many different types of collagen molecules are there?
how many distinct types of collagen are there?

A

42.
over 40.
19.

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21
Q

tell about the molecular structure of collagen

A

long, stiff, triple stranded, helical structure. 3 collagen peptide chains (alpha chains) wound around each other.
Has distinct primary amino acid sequence motif (Gly-X-Y) with X often being proline and Y often being a hydroxyproline

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22
Q

Why is glycine the only amino acid that is on the very inside of collagen?

A

It’s the simplest AA and is the only one that can fit in the tight space in the crowded interior.

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23
Q

How is procollagen converted to collagen?

A

by cleaving AAs at N and C terminus of protein

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24
Q

Can prolines be modified post-translation?

A

yes, hydroxylated to hydroxyproline (also can have lysines and hydroxylysines).

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25
Q

What are the steps to maturation of collagen fibers?

A

Synthesis of pro-alpha chain, hydroxylation of selected prolines and lysines, glycosylation of selected hydrolysines (OH off, sugar on), formation of procollagen triple helix, self-assembly of three pro-alpha chains together, secretion from ER/Golgi compartment, cleavage of pro peptides, then self-assembly into fibril, followed by aggregation of collagen fibrils to form a collagen dimer

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26
Q

What are the important collagen genes?

A

Type I collagen genes: COL1A1 (Chr 17), COL1A2 (Chr 7) - encode 2 alpha1 chains and 1 alpha 2 chain to form triple stranded helical collagen

Type V collagen genes: COL5A1 (Chr 9), COL5A2 (Chr 2), COL5A3 (Chr 19).

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27
Q

What is the genetic structure of collagen (genes)?

A

genes 44kb in size, about 50 exons, exons 54 nucleotides in length (18 AAs, which are 6 Gly-X-Y repeats)

28
Q

What is the mutation in osteogenesis imperfecta?

A

mutation in type I collagen (COL1A1, COL1A2)

29
Q

How many types of osteogenesis imperfecta are usually apparent at birth?

A

Types I through IV (different types of OI, not type collagen genes)

30
Q

List all pertinent facts of type I osteogenesis imperfecta

A
  • OI type I = autosomal dominant w/ variable expressivity (90% penetrance for fractures), mild, variable expressivity. osteopenia (lower bone density) and fractures, dentinogenesis imperfect (bad tooth development), blue sclera of eye throughout life, hearing loss in 50% of adult patients (age-related), oldest documented case from 1,000 BC mummy, most common type of OI, 1:30k, 50% reduction in Type I collagen. Nonsense mutations (premature stop codon), frameshift/splicing errors in COL1A1, decreased alpha1 chains. mutation is in 1 of the COL1A1 genes (other gene works) so 50% of normal amt of alpha1 protein made, triple helix formation greatly reduced, fractures from minimal trauma. Limb deformities from fractures, bowing of limbs (common), hyper mobility (small joints of hands and feet), spontaneous improvement in adolescence w/ reduced amt of fractures, exaggerated postmenopausal bone loss
31
Q

List all pertinent facts of type II osteogenesis imperfecta

A
  • OI type II = severe type, usually death in perinatal period, extreme bone fragility, intrauterine death/early infant death (20% stillborn, 90% deceased by 4 wks), usually new mutation (autosomal dominant), mutations in COL1A1 or COL1A2), missense mutations in which the glycine AA is replaced by another AA residue (structural protein defect), phenotype depends on position and nature of glycine substitution (differentiates OI types II and IV)
32
Q

List all pertinent facts of type III osteogenesis imperfecta

A

OI type III = autosomal dominant (rare autosomal recessive found in consanguinity and Africa), mutations in COL1A1 or COL1A2, increased collagen turnover (severe/progressive skeletal deformities, blue sclera at birth but more normal by adolescence or adulthood, fractures present in most cases at birth and occur frequently during childhood), generalized osteopenia, poor longitudinal growth (below 3rd percentile in height for age and sex), progressive kyphoscoliosis develops in kid and worse into adolescence, no hearing impairment, 1/3 survive long-term, death from complications of severe bone fragility and skeletal deformity

33
Q

List all pertinent facts of type IV osteogenesis imperfecta

A

autosomal dominant, most clinically variable (mild to severe skeletal osteopenia), fractures may occur at birth or not until adulthood, SIGNIFICANT BOWING OF LEGS AT BIRTH MAY BE THE ONLY FEATURE, mutations in COL1A1 or COL1A2 genes.

34
Q

How many types of osteogenesis imperfecta are there?

A

I-VII

35
Q

summary of Osteogenesis imperfecta

A 
Type I (mild)- mutations in COL1A1, autosomal dominant, bone Fx, teeth, blue sclera, deafness 50% of adults, nonsense/frameshift/splicing mutations.
Type II (severe)- extreme bone fragility, lethal in 90% by 4 wks, missense mutations in COL1A1 or COL1A2
Type III (severe)- mutations as above for Type II, but can live longer.
Type IV (variable)- mutations in COL1A1 or COL1A2
36
Q

What do symptoms of undiagnosed Osteogenesis Imperfecta also look like?

A

child abuse: evidence of bruising, varied types of fractures (old fractures in various stages of healing).
bones can appear normal on X-ray

37
Q

How to make sure of osteogenesis imperfecta vs child abuse?

A

obtain family history (indications of mild family disorder), look for clinical features of OI (sclerae, teeth, bruising, barrel-shaped chest, scoliosis), consult a professional w/ OI experience.

38
Q

What is the mutation in Ehlers-Danlos Syndrome?

A

mutation in Type V collagen, in the genes encoding alpha chains of type V collagen

39
Q

What are the characteristics of Ehlers-Danlos syndrome?

A

group of disorders marked by extremely loose joints, hyperelastic skin (bruises easily), easily damaged blood vessels.

40
Q

What type of inheritance is Ehlers-Danlos syndrome?

A

Autosomal dominant

41
Q

What are the diagnostic criteria of Ehlers-Danlos?

A

Skin hyperextensibility, widened atrophic scars, joint hyper mobility, positive family history (3 of 4 needed).

42
Q

What are the 3 types of Ehlers-Danlos syndrome?

A

Classic (mutations in COL5A1, COL5A2)
Hypermobility (least severe)
Vascular type (most severe- 48 yrs avg, type 3 collagen)

43
Q

What is the mutation for Ehlers-Danlos syndrome that ‘s most common? what percentage of EDS patients does it affect?

A

mutations in COL5A1 or COL5A2, 50% of patients.

other 50% not identified, but all mutations are truncated collagen proteins and glycine substitution mutations.

44
Q

Classic Ehlers Danlos summary

A

Clinical presentation- extremely loose joints, hyper elastic skin (that bruises easily), easily damaged blood vessels.
Mutations in genes encoding alpha chains of Type V collagen: COL5A1, COL5A2

45
Q

What are the tall stature syndromes?

A

Marfan Syndrome = fibrillin (FBN1 gene)
Homocystinuria = cystathionine Beta-synthase (CBS gene)
Beckwith-Wiedemann Syndrome = growth syndrome deletion of imprinted genes on chromosome 11p15.5

46
Q

What’s Marfan syndrome?

A

systemic CT tissue disorder. Manifests as skeletal, ocular and cardiovascular defects (80% mitral valve prolapse) (dilation of aortic root seen in 50% children and 70-80% adults) (aortic tear may occur), autosomal dominant.

47
Q

What are characteristics of Marfan’s individuals?

A

unusually tall (97th percentile), long limbs with long and thin fingers, hyperextension of joints, upward lens dislocation, abnormal indentation of sternum (pectus excavatum), scoliosis, arm span exceeds height.

48
Q

What is the genetic mutation in Marfan syndrome?

A

mutation in fibrillin (FBN1) on chromosome 15, which is a major element in elastic and non-elastic tissues.
most mutations are unique, there are over 500 FBN1 mutations known (30% de novo mutations, 70% of mutations are missense)

49
Q

What happens in Marfan’s because of the mutation in FBN1?

A

bc it’s involved in forming elastic fibers (abundant in ligaments, aorta and lens), abnormal fibrillin aggregates in microfibrils and impacts structural integrity.
Also, binds to transforming growth factor (TGF-B) and keeps it sequestered. TGF-B has deleterious effects on vascular smooth muscle development and integrity. Leads to release of proteases that degrade elastin.

50
Q

Summary Marfan Syndrome

A

inherited as dominant trait, mutations in fibrillin (FBN1).
tall stature, arachnodactyly (long fingers), hyperextension of joints, upward lens dislocation, arm span exceeds height, aorta aneurysm.

51
Q

What is the mutation in homocystinuria?

A

methionine (an essential AA), is converted to cysteine in a biochemical pathway. the intermediate is homocysteine. Homocystinuria has a deficiency of cystathionine beta-synthase (CBS).

52
Q

What is the type of inheritance of homocystinuria?

A

autosomal recessive

53
Q

What does the mutation in homocystinuria lead to?

A

increased urinary excretion of homocysteine with increased plasma homocysteine and methionine.

54
Q

What are the clinical features of homocystinuria?

A

excessive height and length of limbs, lens dislocation (but lens dislocation is downward), vascular abnormalities, (also resembles Marfans w/ arachnodactyly, pectus excavatum)

55
Q

How do you treat homocystinuria?

A

restrict dietary Methionine (elevated levels of MET are toxic to nervous system, elevated levels of HCY = increased risk of heart and vascular disease).
Supplement with Cysteine (CYS

56
Q

What is Beckwith-Wiedemann syndrome?

A

congenital growth disorder that causes large body size, large organs and other symptoms, overgrowth disorder usually present at birth.
(formerly called EMG syndrome. Exomphalos= abdominal hernia defects, Macroglossia= large tongue, Gigantism= large body)

57
Q

What is the Beckwith-Wiedemann etiology?

A

Most have no detectable chromosomal abnormality, some have mutations on chromosome 11p15.5; [uniparental disomy (extra paternal copy)] or several other gene candidates.

58
Q

What is the inheritance of Beckwith-Wiedemann syndrome?

A

complex and variable depending on families:

  • autosomal dominant w/ variable penetrance
  • partial trisomy
  • altered methylation
59
Q

What are clinical presentations of Beckwith-Wiedemann syndrome?

A

pre and post natal overgrowth

  • increased rate of growth during later part of pregnancy and first few yrs postnatally but eventually normal height.
  • may show hemihypertrophy- abnormal assymetry btwn left and right side of body, occurring when one part of body grows faster than normal.
  • NEONATAL HYPOGLYCEMIA
  • 1:13.7k
60
Q

What is the importance of Beckwith-Wiedemann syndrome?

A
  • infant mortality rate = 21% bc of congestive heart failure, sleep apnea, infantile respiratory distress syndrome.
  • increased risk of embryonal tumors,
  • Treatment for neonatal hypoglycemia (transitory, may cause permanent brain damage if unrecognized)
  • increased risk of childhood tumors (10% develop malignancies, increased with hemihypertrophy) (most common= Wilms, adrenal cortical carcinoma, hepatoblastoma)
61
Q

what’s the prognosis of beckwith-wiedemann syndrome?

A

very good, children w/ BWS generally do well, grow up to heights expected based on parental heights, no significant developmental delays compared to siblings.

62
Q

acromegaly

A

GH release after bone growth, causes bones in hands and feet and face to grow

63
Q

prader-willi syndrome

A

most common form of genetic obesity, first recognized microdeletion syndrome, genomic imprinting disorder, UPD disorder. short stature

64
Q

noonan syndrome

A

autosomal dominant, looks similar to turner syndrome.
short, PTPN11 (non-receptor protein tyrosine phosphatase) which now won’t allow conversion of inactive protein to active.

65
Q

classic growth hormone deficieny

A

short stature, skeletal maturation delay

66
Q

Laron syndrome

A

autosomal recessive, growth hormone receptor mutation, results in GH insensitivity, patient doesn’t respond to GH.

Musculoskeletal (10 decks)

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