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Genetics of Vascular Diseases Jake Lusis 3-730 MRL Jlusis@mednet.ucla.edu. Carl Miller, ~1938, Oslo County Hospital, Norway. Inheritance of: Cholesterol level (mg/dl): Tendon xanthomas: Early coronary artery disease (under 55 years of age):. 330 210. 210. 200. 210. 180. 430. 410.

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slide1

Genetics of Vascular Diseases

Jake Lusis

3-730 MRL

Jlusis@mednet.ucla.edu

slide3

Carl Miller, ~1938, Oslo County Hospital, Norway

Inheritance of:

Cholesterol level (mg/dl):

Tendon xanthomas:

Early coronary artery disease (under 55 years of age):

330210

210

200

210

180

430

410

490

190

420

460

slide5

Inheritance of:

Cholesterol level (mg/dl):

Tendon xanthomas:

Early coronary artery disease (under 55 years of age):

210230

190

400

210

210

420

180

430

490

420

810

420

170

This individual died from severe CAD at age 7

slide6

Lecture delivered in Sweden Dec 9, 1985 when they received the Nobel Prize in Physiology. Published in Science, 232, 34-47, 1986

slide7

Experiments with 125I-LDL and skin fibroblasts

skin fibroblasts from normal and FH individuals

add labeled 125I-LDL ( )

incubate to allow binding

wash away unbound LDL and follow label

- 125I-LDL on surface can be displaced from cells by anionic polymers

- 125I-LDL that has been internalized cannot be displaced from cells

- 125I-LDL that has been degraded to amino acids is soluble in tricholoroacetic acid

slide11

Cloning of the Human LDL Receptor

isolate plasma membrane

cultured skin fibroblasts

purify such that a single protein remains upon electrophoresis

extract proteins with detergent and subject to chromatography

125I-LDL bound

digest the protein and sequence the resulting peptides

-ASN-PHE-THR-SER-

probe cDNA and genomic libraries. Confirm identity of clones by sequencing and expression studies

based on the amino acid sequence, synthesize corresponding oligonucleotide probes

….CACTCGACAGCGAAC...

lessons from familial hypercholesterolemia
Lessons from familial hypercholesterolemia
  • Studies of an uncommon disease (FH) can have important implications for a common disease (coronary artery disease)
  • Genetics studies of clinical traits can lead to an understanding of basic biologic mechanisms (receptor mediated endocytosis, cholesterol homeostasis) as well as new therapies (statins).
slide18

Schematic of the approach generally utilized for positional cloning

BACs

Normal

Candidate

cDNAs

Physical

Mapping

and

Cloning

Families

Finer

Genetic

Mapping

..A A C T C

Linkage

Analysis

Transcript

Identification

Mutation

Search

+

..A A G T C

Mutation

Genetic

Markers

slide20

Marfan Syndrome

-autosomal dominant disorder characterized by weakened connective tissue

-most life-treatening is aortic dissection (an aneurysm of the aorta)

-other symptoms include mitral valve prolapse, emphysema-like lung disease, and

ocular and skin disorders

-patients tend to be tall and lanky, with very long limbs, fingers and toes

slide21

Fibrillin 1 Gene Mutated in Marfan Syndrome Patients

  • Single-strand conformational polymorphism screen
  • DNA sequence
slide22

Letter

Nature Genetics33, 407 - 411 (2003) Published online: 24 February 2003;

Dysregulation of TGF- activation contributes to pathogenesis in Marfan syndrome

Enid R. Neptune1, 2, Pamela A. Frischmeyer2, Dan E. Arking2, Loretha Myers2, Tracie E. Bunton3, Barbara Gayraud4, Francesco Ramirez4, Lynn Y. Sakai5 & Harry C. Dietz2, 6

slide24

Figure 3

Active TGF-B expression and signaling in lung tissue of mice deficient in fibrillin-1.

slide26

Mice deficient in fibrillin-1 have preserved lung cell proliferation but greater apoptosis.

slide27

Model

Fibrillin deficiency

TGFB not sequestered

TGFB activated

Apoptosis in lung, bone overgrowth, etc.

A lesson: Structural matrix elements serve crucial regulatory roles in cytokine activation and signalling

slide33

Article

Nature Genetics34, 383 - 394 (2003)

VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death

Diether Lambrechts1, Erik Storkebaum1, Masafumi Morimoto1, Jurgen Del-Favero2, Frederik Desmet1, Stefan L Marklund3, Sabine Wyns1, Vincent Thijs1, Jörgen Andersson3, Ingrid van Marion4, Ammar Al-Chalabi5, Stephanie Bornes6, Rhiannon Musson4, Valerie Hansen5, Lars Beckman3, Rolf Adolfsson7, Hardev Singh Pall4, Hervé Prats6, Severine Vermeire1, Paul Rutgeerts1, Shigehiro Katayama8, Takuya Awata8, Nigel Leigh5, Loïc Lang-Lazdunski9, Mieke Dewerchin1, Christopher Shaw5, Lieve Moons1, Robert Vlietinck1, 10, Karen E Morrison4, Wim Robberecht1, Christine Van Broeckhoven2, Désiré Collen1, Peter M Andersen3 & Peter Carmeliet1

slide34

Figure 1.Genetic association of VEGF with ALS.

Figure 1.Genetic association of VEGF with ALS.

VEGF Polymorphisms

slide39

Lesson

Basic vascular biology studies (regulation of VEGF expression in response to hypoxia) can lead to an understanding of a complex disease