Tissue-selective Imprinting

Question 1

What is genomic imprinting?

Answer 1

The epigenetic silencing of one allele (either of paternal or maternal origin) in a genetic locus.

Question 2

Is it common in humans?

Answer 2

No, it only occurs in a small amount of loci.

Question 3

What is the process followed?

Answer 3

1. Epigenetic silencing of a gene.

2. During meiosis, all epigenetic marks are removed, and then repositioned in the gametes in a parent-specific manner.

Question 4

What does “in a parent-specific manner” mean?

Answer 4

There are a few genes that are normally imprinted in humans. For each imprinted locus, normally one allele is imprinted, and the other is not. The imprinted allele has to be inherited from a parent of the same gender EVERY TIME. E.g, allele A is imprinted in maternally derived chromosomes EXCLUSIVELY whilst allele B is always imprinted in paternally derived chromosomes. In order for every child to have the same imprinting pattern with its parents (one gene imprinted, the other not), during meiosis, the following procedure takes place: If the imprinted gene is maternally derived (like gene A), all of the mother’s gametes will have imprinted genes. That means that, all of the father’s gametes will have a non-imprinted gene in that locus. As a result, the child will have one imprinted and one non imprinted gene in that specific locus. Exception: Uniparental disomy

Question 5

What is the Albright’s hereditary osteodystrophy (AHO) phenotype?

Answer 5

It is the coexistence of short stature, shortened fourth and fifth metacarpals, rounded facies (full cheeks), and also ectopic ossification.

Question 6

What causes the AHO phenotype?

Answer 6

Presence of one GNAS1 gene instead of two during embryogenesis. TWO genes are required in that locus for normal phenotype. With one gene mutated and one present, the AHO phenotype develops. GNAS1 is a gene affected by genomic imprinting. In general those genes need to be BOTH non mutated in the embryogenic period in order for the phenotype to be normal. If a mutation affects either allelle, maternal or paternal, it reinforces the preponderance of paternal or maternal expression respectively. So, 1) if we get more paternal expression, the phenotype is going to be bigger and have the tendency to consume nutrients, like in Beckwith-Wiedemann syndrome OR 2) if maternal expression is greater, it results at a smaller, phenotype that does not need that much nutrients.

Question 7

What happens if paternal GNAS1 is defective?

Answer 7

Only maternal GNAS1 is present during embryogenesis. Thus AHO phenotype develops. The disease is term Pseudopseudohypoparathyroidism-we will later see why.

Question 8

What happens if maternal GNAS1 is defective?

Answer 8

Only paternal GNAS1 present->AHO phenotype develops. THE DIFFERENCE IS that the maternal GNAS1 is NORMALLY SELECTIVELY EXPRESSED in some tissues. That means that normally, in some tissues, the paternal gene is silenced. This is called selective tissue imprinting, and it is entirely new, we do not know how it happens. The point here is that we lose the maternal expression in specific tissues thyroid, gonadotropes, renal tubule). As a result, we have resistance in TSH, PTH and GnRH that manifest as low calcium, mild intellectual defect and hypogonadism. This is termed Pseudohypoparathyroidism type IA.

Question 9

What’s with the names?

Answer 9

The name Pseudohypoparathyroidism is right, because it refers to clinical expression of hypoparathyroidism with normal PTH, hence resistance to PTH. Type IA is due to maternal GNAS1 mutation that prevents it from being expressed in thyroid, renal tubules and gonadotropes. As the paternal gene is not normally epressed there, we get the symptoms. Type IB is an imprinting defect ONLY in renal tubules, but not in thyroid and gonadotropes. So the name is correct for Type IB as well. However, the name Pseudopseudohypoparathyroidism is indeed confusing. It was created because in this disease, the AHO phenotype was observed, much like in Pseudohypoparathyroidism Type IA. The confusing thing was that PTH and calcium were fine.

Question 10

Make a summary.

Answer 10

Pseudohypoparathyroidism

• Type IA: Sx AHO + tetany + intellectual impairment +hypogonadism, Labs Hypocalcemia with elevated PTH
• Type IB: Sx tetany, Labs Hypocalcemia with elevated OTH

Pseudopseudohypoparathyroidism: AHO, Labs OK

• > One gene defective in embryogenesis: Pseudohypoparathyroidism type IA (maternal), PSeudopseudohypoparthyroidism (paternal)
• > Only renal tubule expression affected: Pseudohypoparathyroidism type IB.