Genetics Of SHH

Question 1

What are sonic hedgehog genes?

Answer 1

Sonic hedgehog genes induce cell proliferation and are involved in tissue patterning

•Expressed in a wide range of tissues including:
– Neural ectoderm such as the notochord and ventral floor plate of the
neural tube > DORSAL VENTRAL PATTERNING
– Hair follicle, tooth, lung and pancreas development

•SHH is expressed at different temporal periods during development to control different areas

•SHH also establishes the zone of polarizing activity
– Involved in limb patterning

Question 2

What are the defects in sonic hedgehog ?

Answer 2

Defects in Sonic Hedgehog (SHH)
signaling pathway may result in several different disorders

• SHH protein is cleaved to an active N-terminal form, which is then modified by the addition of cholesterol.
• The normal action of PTCH is to inhibit SMO, but when PTCH is bound by SHH this inhibition is removed activating downstream signaling.
• GLI protein and CREBBP interact and activate gene expression by binding to regulatory sequence on the DNA.

Question 3

How can SHH lead to holoprosencephaly?

Answer 3

• Heterozygous mutations leading to haploinsufficiency of
SHH may result in a form of holoprosencephaly.
– These are loss of function mutations; AD

• There is wide clinical variability, within the same family affected individuals may present with holoprosencephaly, microcephaly facial abnormalities including cyclopia, cleft lip/palete, hypotelorism (decreased interorbital distance)

• Effect could be limited to single central maxillary incisor to no
observable phenotypic observation at all
– Compare and contrast:
– variable expressivity to incomplete penetrance

Question 4

How can hypertelorism be achieved from SHH defects?

Answer 4

Increasing SHH in the frontal nasal prominence promotes mediolateral expansion of the face and ventral forebrain.

Also increased distance between the eyes (hypertelorism)

Question 5

True facial duplications are…

Answer 5

Extremely rare in humans suggesting that they may be associated with other developmental disturbances that are incompatible with life

Question 6

What is the purpose of HOX genes?

Answer 6

HOX genes pattern the anterior-posterior axis of the vertebrate embryo, and pattern the anterior- posterior axis of the vertebrate limb bud.

• In the limb bud, HOX gene expression is established as a result of the generation of a gradient of Sonic Hedgehog protein that is produced by the Zone of Polarizing Activity (ZPA)

Question 7

Mutations affecting expression (overexpression)…

Answer 7

of SHH in the limb bud may be a cause o f preaxial polydactyly

Question 8

What is occurrence of holoprosencephaly?

Answer 8

Holoprosencephaly (HPE)
– Incidence - 1/5,000 to 1/10,000
– One cause is haploinsufficiency of SHH

Question 9

What are the correlations of SHH mutations?

Answer 9

Phenotype/genotype correlation for SHH mutations
is difficult to establish (modifier effects of other
genes

– A spectrum of severity: mild effects such as single incisor; moderate effects such as cleft lip and palate; to severe effects such as cyclopia.

Question 10

What is Smith-Lemi-Opitz syndrome?

Answer 10

Smith-Lemi-Opitz Syndrome (1/20,000 to 1/40,000
births):
– Mutation in gene encoding 7-dehydrocholestrol reductase
– Microcephaly, mental impairment, malformation of
mesodermal origin, syndactyly, and polydactyly

Question 11

Explain the spectrum of the phenotypes

Answer 11

Very rare syndromes

Some common phenotypes Explained by common pathway

This explanation established after molecular identification, and elucidation of the SHH signaling pathway