GNAS complex locus

The gene product is involved cGMP signal transduction. Imprinting influences which isofoms are transcribed, spliced, and translated. Deficiency causes pseudohypoparathyroidism, Albright osteodystrophy and pituitary tumor.

Gene Structure

The gene is located on chromosome 10 (20q13.2), spans approximately 74kb, and consists of 13 exons. Four splice variants are known. The differ predominantly in their first exon.

The protein product of the splice variant with the most upstream first exon is also known as NESP55. Exons 2-13 are also transcribed but translation is terminated by a stop codon in exon 1. The function of NESP55 remains to be elucidated.

The protein product of the splice variant with the most downstream transcription start is called Gs, a component of G-coupled receptors. Exons 2-13 express all essential components of normal protein function.

A third splice variant with an exceptional large exon 1 is named XLAS. As exons 2-13 are identically expressed its function seems to be similar to Gs.

Still an other exon 1, dubbed 1A, with a different pattern of imprinting is postulated. The understanding of gene function is further convoluted by the discovery of a NESP55 complementary transcription product.

Genomic imprinting ensures different gene products from the maternal and paternal alleles expressed in renal tubules. Genomic imprinting is an epigenetic phenomenon associated with methylation of the promoter (at cytidines within CpG dinucleotides) that inactivates distinct splice variants. Normally the splice variants XLAS and A1 are inactivated on the maternal allele whereas NESP55 is inactivated on the paternal allele.

Interpretation

Mutations that affect the coding region of the Gs splice variant result in Albright hereditary osteodystrophy (AOH) characterized by skeletal abnormalities and endocronological dysfunctions. If inherited from father AOH is associated with pseudopseudohypoparathyroidism (PPHP) whereas maternal transmission results in several endocrinological dysfunctions including thyreotropin resistance and pseudohypoparathyroidism (PHP1A).

If both alleles exhibit paternal imprinting (lack of methylation) of the promotor of the splice variant A1, then in the distal tubule insufficient Gs will be transcribed and a PTH resistence of the kidney ensues (PHP1B).

Activating somatic mutations result in McCune-Albright syndrome. The mosaic of normal und mutated cells makes a molecular genetic diagnosis difficult.

Genetests:

Clinic	Method	Carrier testing
	Turnaround	5 days
	Specimen type	genomic DNA

Clinic	Method	Massive parallel sequencing
	Turnaround	25 days
	Specimen type	genomic DNA

Clinic	Method	Highly sensitive PNA-based PCR
	Turnaround	25 days
	Specimen type	genomic DNA

Clinic	Method	Antisense sequencing
	Turnaround	25 days
	Specimen type	genomic DNA

Clinic	Method	Genomic sequencing of the entire coding region
	Turnaround	25 days
	Specimen type	genomic DNA

Clinic	Method	Methylation test
	Turnaround	25 days
	Specimen type	genomic DNA

Clinic	Method	Multiplex Ligation-Dependent Probe Amplification
	Turnaround	25 days
	Specimen type	genomic DNA

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