Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations

Abstract

Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are two rare autosomal dominant disorders caused by loss-of-function mutations in the imprinted Guanine Nucleotide Binding Protein, Alpha Stimulating Activity (GNAS) gene, coding G s α. PHP1A is caused by mutations in the maternal allele and results in Albright's hereditary osteodystrophy (AHO) and hormonal resistance, mainly to the parathormone (PTH), whereas PPHP, with AHO features and no hormonal resistance, is linked to mutations in the paternal allele. This study sought to investigate parental transmission of GNAS mutations. We conducted a retrospective study in a population of 204 families with 361 patients harboring GNAS mutations. To prevent ascertainment bias toward a higher proportion of affected children due to the way in which data were collected, we excluded from transmission analysis all probands in the ascertained sibships. After bias correction, the distribution ratio of the mutated alleles was calculated from the observed genotypes of the offspring of nuclear families and was compared to the expected ratio of 50% according to Mendelian inheritance (one-sample Z-test). Sex ratio, phenotype of the transmitting parent, and transmission depending on the severity of the mutation were also analyzed. Transmission analysis was performed in 114 nuclear families and included 250 descendants. The fertility rates were similar between male and female patients. We showed an excess of transmission from mother to offspring of mutated alleles (59%, p = .022), which was greater when the mutations were severe (61.7%, p = .023). Similarly, an excess of transmission was found when the mother had a PHP1A phenotype (64.7%, p = .036). By contrast, a Mendelian distribution was observed when the mutations were paternally inherited. Higher numbers of females within the carriers, but not in noncarriers, were also observed. The motherspecific transmission ratio distortion (TRD) and the sex-ratio imbalance associated to PHP1A point to a role of G s α in oocyte biology or embryogenesis, with implications for genetic counseling.

Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion

“…2). Similar to the findings in PHP1A/PPHP females, ( 26 ) the odds of transmitting the mutant, not the wild‐type, STX16/GNAS allele to the next generation is therefore approximately 2:1.…”

“…A recent study had revealed that females affected by PHP1A or PPHP are more likely to transmit the allele with disease‐causing GNAS mutation instead of the normal allele to their children, particularly if the genetic defect was predicted to severely reduce or abolish Gsα function. ( 26 ) We now sought to determine whether a similar TRD can be observed also for mutations that reduce Gsα function through LOM at GNAS exon A/B alone or LOM at all three maternal DMRs. We therefore investigated first all available members of kindred F that had facilitated the initial identification of genetic locus for AD‐PHP1B and the subsequent discovery of the 3‐kb STX16 deletion on the maternal allele as the most frequent cause of this disorder.…”

“…Furthermore, PHP1A patients with GNAS mutations that are predicted to reduce, but not abolish, Gsα function had a comparable number of affected and unaffected children, whereas mothers with severe Gsα mutations had considerably more affected than unaffected offspring. ( 26 ) Observations similar to those for PHP1A/PPHP females had been previously made for several other genetic disorders, including the long QT syndrome, ( 27,28 ) but the underlying mechanism(s) that causes TRD in these families remains unknown.…”

“…S1). This suggested that TRD is observed not only for the offspring of females affected by either PHP1A or PPHP ( 26 ) but also for women carrying the 3‐kb STX16 deletion that causes LOM at GNAS exon A/B when located on the maternal allele.…”

“…A recent retrospective analysis revealed evidence for transmission ratio distortion (TRD) for inactivating mutations involving the maternal GNAS exons 1–13. ( 26 ) In that report, females affected by PHP1A or PPHP, ie, patients with AHO features in the presence or absence of hormonal resistance, showed a significantly higher likelihood of passing the underlying genetic mutation to their children. In contrast, males affected by PHP1A/PPHP passed the mutant allele to about half of their offspring as expected for a Mendelian disorder.…”