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.
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.
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.
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 |
Pseudohypoparathyroidism | ||||
Albright hereditary osteodystrophy | ||||
GNAS | ||||
Pseudohypoparathyroidism type IB | ||||
GNAS | ||||
GNAS-AS1 | ||||
STX16 | ||||
1. |
Liu J et al. (2000) A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. |
2. |
Hayward BE et al. (2001) Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. |
3. |
Freson K et al. (2002) Pseudohypoparathyroidism type Ib with disturbed imprinting in the GNAS1 cluster and Gsalpha deficiency in platelets. |
4. |
Jan de Beur S et al. (2003) Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1. |
5. |
Hayward BE et al. (1998) The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. |
6. |
Hayward BE et al. (1998) Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. |
8. |
Orphanet article Orphanet ID 122194 |
9. |
NCBI article NCBI 2778 |
10. |
OMIM.ORG article Omim 139320 |
11. |
Wikipedia article Wikipedia EN (GNAS_complex_locus) |