18.03.05 AD - Haploinsufficiency

Question 1

Define haploinsufficiency.

Answer 1

Most autosomal genes are not dosage sensitive. In a small number f cases, both copies need to be functional in otder to express a normal phenotype.

59% of the normal gene product/expression/activity is not enough. Inactivation/loss of a single allele produces the phenotype.

Question 2

How many haploinsufficient genes are there estimated to be?

Answer 2

~300

Question 3

What genotype-phenotype correlation indicates that a gene may be haploinsufficient?

Answer 3

All mutations types produce the same phenotype suggesting loss as opposed to gain of function.

AD pattern observed (equal males and females affected)

Question 4

What types of genes may express haploinsufficiency? Give examples.

Answer 4

1. Highly expressed genes - e.g. ELN. 1 gene sufficient for lung and skin function but not for the heart as that requires a large amount of expression. Loss here = SVAS.
2. Dosage sensitive genes (majority of HI genes). Relative rather than absolute levels are important. Genes that act alone rarely show dosage effects.
   a) Genes in quantitative signalling system
   b) Gene products that compete to determine a developmental/metabolic switch
   c) Genes that cooperate in interactions with fixed stoichiometry. Many structural proteins.
3. Imprinted genes

Many associated with systemic wide-spectrum roles such as development, signalling and transcriptional regulation. 2/3 mutations in TF are dominant or semi-dominant.

Question 5

Why do some disease that show AD inheritance due to HI also have recessive forms. Give an example.

Answer 5

Marfan syndrome (FBN1, 15q21.1)

• complete loss of one allele
• 50% reduction in both alleles.

Question 6

What are some of the possible effects of inheriting two dominant alleles that show haploinsufficiency?

Answer 6

Lethality

More severe form of the disease

Question 7

What evidence is there to suggest that there is selective pressure to maintain HI genes at their correct copy number?

Answer 7

HI genes less likely than average to be situated in segmentally duplicated regions, which are prone to mutation by NAHR.

Question 8

Give some examples of haploinsufficiency in gene disorders.

Answer 8

1. Familial hypertrophic cardiomyopathy/HCM (MYH7)
2. Alagille syndrome type 1 (JAG1)
3. Cleidocranial dystosis (RUNX2)
4. Aniridia (PAX6)
5. AD optic atrophy (OPA!)
6. GLUT1 deficiency sydnrome (SLC2A1)
7. HNPP (PMP22)

Question 9

Give examples of haploinsufficiency in contiguous gene deletion syndromes.

Answer 9

1. Overlap with single-gene defects e.g. PAX6 giving anirida in WAGR syndrome
2. TBX1 in 22q11.2 deletion syndrome
3. Cri-du-chat caused by multiple gene deletion in 5p15. More proximal region 5p15.3 associated with cat-like cry and speech delay.
4. ELN in Williams syndrome giving SVAS.

Question 10

Give examples of haploinsufficiency in cancer.

Answer 10

1. p53
2. PTEN
3. BRCA1

Question 11

What is the incidence and clinical phenotype of left-ventricular hypertrophy?

Answer 11

~1 in 500

Wide range of phenotype, even within families. 
Hypertension
Palpitations
Progressive heart failure
Heart congestions
Suddent cardiac death

Question 12

Give three examples of genes associated with familial hypertrophic cardiomyopathy/HCM.

Answer 12

20+ genes involved in structure and function of sarcomere in the heart.

70-80% of mutations in MYH7 and MYBPC3
10% in TNNT2 and TNNI3

Four gene panel has 50% sensitivity.

Question 13

How is haploinsufficiency demonstrated by MYBPC3 in HCM?

Answer 13

Lack of truncated MYBPC3 proteins into HCM cardiac tissues

A lowered expression of full-length protein.

Question 14

What explains some of the phenotypic variability in HCM?

Answer 14

Interaction of multiple genes in a large system, requiring co-operation and fixed stoichiometry between gene products, characteristic of a haploinsufficiency syndrome.

Question 15

DCM is assoicated with haploinsuffiency of which gene?

Answer 15

LMNA (1q22)

Question 16

What are the clinical features of Alagille syndrome?

Answer 16

Multi-system phenotype, involving heart, liver, ete and skeletal defects

Lack of bile ducts, cardiac abnormalities and typical facies.

Question 17

Which genes are associated with Alagille syndrome.

Answer 17

> 89% JAG1 defects (~7% CNV) at 20p12
1-2% have NOTCH2

High de novo rate (50-70%)

Question 18

Which gene is associated with cleodocrainal dystosis? What is the phenotype of this disorder?

Answer 18

RUNX2 - TF for differentiation and morphogeneisis of osteoblasts required for skeletal development.

General skeletal disorder involving missing or partial collarbones

Question 19

Which gene is associated with aniridia? What is the phenotype of this disorder?

Answer 19

PAX6 (11p13)- highly conserved, control gene for eye development

Lack of irises and other eye defects e.g. cataracts, optic nerve dysfunction.

Homozygous mutation - complete lack of eye formation

Question 20

Which gene is associated with AD optic atrophy? What is the phenotype of this disorder?

Answer 20

OPA1 gene function is not fully known, but is involved in mitrochondrial membrane complexes.

Progressive loss of visual acuity with variable optic manifestation, onset in childhood, often blindness in adulthood.

Question 21

Which gene is associated with GLUT1 deficiency syndrome? What is the phenotype of this disorder?

Answer 21

SLC2A1 - required for transport of glucose across blood-brain barrier.

hererogenous neurological condition, infantile seizures.

Treated with a ketogenic diet.

Question 22

Which gene is associated with HNPP? What is the phenotype of this disorder?

Answer 22

PMP22
80% have a deletion
Repeated focal pressure neuropathies.