GALT is an enzyme involved in the conversion of galactose to glucose (galactose-1-phosphate to glucose-1-phosphate). Mutation of this gene leads to decreased enzyme activity and a buildup of galactose metabolities including galactose-1-phosphate and galactitol in multiple cell types. These products leads to cell damage or death through unknown mechanisms. females develop reproductive dysfunction ranging from primary amenorhhea to premature ovarian failure.
NCBI Summary:
Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
General function
Enzyme, Transferase
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Follicle development
Comment
Primary ovarian insufficiency in classic galactosemia: current understanding and future research opportunities. Thakur M et al. (2017) Classic galactosemia is an inborn error of the metabolism with devastating consequences. Newborn screening has been successful in markedly reducing the acute neonatal symptoms from this disorder. The dramatic response to dietary treatment is one of the major success stories of newborn screening. However, as children with galactosemia achieve adulthood, they face long-term complications. A majority of women with classic galactosemia develop primary ovarian insufficiency and resulting morbidity. The underlying pathophysiology of this complication is not clear. This review focuses on the reproductive issues seen in girls and women with classic galactosemia. Literature on the effects of classic galactosemia on the female reproductive system was reviewed by an extensive Pubmed search (publications from January 1975 to January 2017) using the keywords: galactosemia, ovarian function/dysfunction, primary ovarian insufficiency/failure, FSH, oxidative stress, fertility preservation. In addition, articles cited in the search articles and literature known to the authors was also included in the review. Our understanding of the role of galactose metabolism in the ovary is limited and the pathogenic mechanisms involved in causing primary ovarian insufficiency are unclear. The relative rarity of galactosemia makes it difficult to accumulate data to determine factors defining timing of ovarian dysfunction or treatment/fertility preservation options for this group of women. In this review, we present reproductive challenges faced by women with classic galactosemia, highlight the gaps in our understanding of mechanisms leading to primary ovarian insufficiency in this population, discuss new advances in fertility preservation options, and recommend collaboration between reproductive medicine and metabolic specialists to improve fertility in these women.//////////////////
Swartz WJ, et al reorted the galactose inhibition of ovulation in mice.
Clinical evidence suggests an association between galactosemia and premature
ovarian failure. In the present study, adult female mice were fed a diet consisting
of 50% galactose for either 2, 4, or 6 weeks. At all times there was a decrease in
the normal ovulatory response, as evidenced by a reduction in the number of
corpora lutea when compared with controls. Additionally, the exposure of
galactose-treated mice to a superovulatory regimen of pregnant mare's serum
gonadotropin (PMSG) and human chorionic gonadotropin (hCG) failed to induce
an increased ovulatory response. Morphologic alterations, such as the increase in
interstitial tissue and the appearance of lipofuscin, coupled with the failure to
respond to exogenous gonadotropins, suggest that the reduced ovulatory response
may be occurring at the level of the ovary. This effect, however, is reversible with
cessation of galactose treatment.
Liu G, et al 2000 reviewed galactose metabolism and ovarian toxicity.
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It has been found that the mammalian ovary is particularly susceptible to
damage from the accumulation of galactose and galactose metabolites. The
galactose metabolites Gal-1-P, galactitol, and UDPgal are all considered to be
important in this toxicity and proposed mechanisms include interference with
ovarian apoptosis and gonadotrophin signaling. This review addresses the most
recent scientific findings regarding the possible mechanisms of galactose-induced
ovarian toxicity and also the possible protective role of hormonal and antioxidant
therapy. In addition, the available epidemiologic and scientific evidence linking
galactose intake with risk of ovarian cancer is discussed.
Santoro N. 2001 reviewed research on the mechanisms of premature ovarian failure.
Expression regulated by
Growth Factors/ cytokines, PRL
Comment
Prolactin Signaling Through the Short Form of Its Receptor Represses FOXO3 and its Target Gene Galt Causing a Severe Ovarian Defect. Halperin J et al. Prolactin is a hormone with over 300 biological activities. Although the signaling pathway downstream of the long form of its receptor (RL) has been well characterized, little is known about PRL actions upon activation of the short form (RS). Here, we show that mice expressing only RS exhibit an ovarian phenotype of accelerated follicular recruitment followed by massive follicular death leading to premature ovarian failure (POF). Consequently, RS-expressing ovaries of young adults are depleted of functional follicles and formed mostly by interstitium. We also show that activation of RS represses the expression of the transcription factor FOXO3 and that of the enzyme galactose-1-phosphate urydiltransferase (Galt), two proteins known to be essential for normal follicular development. Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevent Galt expression in the ovary and causes follicular death. Co-expression of RL with RS prevents PRL inhibition of Galt, and the ovarian defect is no longer seen in RS transgenic mice that co-express RL, suggesting that RL prevents RS-induced ovarian impairment. In summary, we show that prolactin signals through RS and causes, in absence of RL, a severe ovarian pathology by repressing the expression of FOXO3 and that of its target gene Galt. We also provide evidence of a link between the POF seen in mice expressing RS, in mice with FOXO3 gene deletion as well as in human with Galt mutation.
Ovarian localization
Comment
Heidenreich RA, et al reported developmental and tissue-specific modulation of rat
galactose-1-phosphate uridyltransferase steady state messenger
RNA and specific activity levels.
They
determined steady state GALT mRNA and specific activity (sp act) in rat liver during postnatal
development. Steady state GALT mRNA levels increase from birth to d 5 and
subsequently decrease toward adult levels. GALT sp act mirrors the mRNA
pattern. A survey of steady state mRNA and GALT sp act of several adult rat
tissues revealed marked tissue differences with a good correlation of the two
parameters. Liver had the highest GALT mRNA and sp act; kidney, ovary, and
heart had similar but lower mRNA and sp act; skeletal muscle and testes had the
least GALT mRNA and enzyme sp act. These findings suggest that genetic
regulation is important in the variable expression of GALT tissue sp act.
Follicle stages
Comment
Phenotypes
POF (premature ovarian failure)
Mutations
2 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment:Kaufman FR, et al reported hypergonadotropic hypogonadism in female patients with
galactosemia.
The authors evaluated gonadal function in 18 female and eight male patients with
galactosemia due to transferase deficiency; it was normal in the males, but 12
females had signs of hypergonadotropic hypogonadism. All female patients had a
46,XX karyotype, normal levels of thyroid hormone and prolactin, and no
anti-ovarian antibodies. The biologic activity of urinary gonadotropins was
normal. Ultrasonography of the pelvis revealed that ovarian tissue was diminished
or absent. Total estrogens increased in one of two patients after administration of
human menopausal gonadotropin. The frequency of hypergonadotropic
hypogonadism was higher in females in whom dietary treatment for galactosemia
was delayed. Clinical course and mean erythrocyte galactose-1-phosphate and
urinary galactitol levels did not correlate with ovarian function. It was concluded that
female patients with galactosemia have a high incidence of ovarian failure due to
acquired ovarian atrophy. Galactose or its metabolites may be toxic to the ovarian
parenchyma, particularly during the immediate neonatal period.
The bioactivity of LH and FSH appear to be unaltered in these patients.///////////////
Modifiers of ovarian function in girls and women with classic galactosemia. Spencer JB et al. Context:Classic galactosemia is a potentially lethal genetic disorder resulting from profound impairment of galactose-1P uridylyltransferase (GALT). More than 80% of girls and women with classic galactosemia experience primary or premature ovarian insufficiency despite neonatal diagnosis and rigorous lifelong dietary galactose restriction.Objective:The goal of this study was to test the relationship between markers of ovarian reserve, cryptic residual GALT activity, and spontaneous pubertal development in girls with classic galactosemia.Design:Cross-sectional with some longitudinal follow-up.Setting:University research environment.Patients:Girls and women with classic galactosemia and unaffected controls, <1 month to 30 years old.Interventions:None.Main Outcome Measures:Plasma Anti-Mllerian Hormone (AMH) and Follicle Stimulating Hormone (FSH) levels, antral follicle counts ascertained by ultrasound, and ovarian function as indicated by spontaneous vs. assisted menarche.Results:More than 73% of the pre- and post-pubertal girls and women with classic galactosemia in this study, ages >3 months to 30 years, demonstrated AMH levels below the 95% confidence interval for AMH among control women of the same age, and both pre- and post-pubertal girls and women with classic galactosemia also demonstrated abnormally low antral follicle counts relative to age-matched controls. Predicted residual GALT activity =0.4% significantly increased the likelihood that a girl with classic galactosemia would demonstrate an AMH level =0.1 ng/mL.Conclusions:A majority of girls with classic galactosemia demonstrate evidence of diminished ovarian reserve by 3 months of age and predicted cryptic residual GALT activity is a modifier of ovarian function in galactosemic girls and women.
Species: human
Mutation name: type: None fertility: None Comment:Bouilly et al. (2016) : Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility.
POI affects1%ofwomenbefore age 40 years, and several genetic causes have been reported.
To date, POI has been considered a monogenic disorder.
Objective: The aim of this study was to identify novel gene variations and to investigate if individuals
with POI harbor mutation in multiple loci.
Patients and Methods: One hundred well-phenotyped POI patients were systematically screened
for variants in 19 known POI loci (and potential candidate genes) using next-generation
sequencing.
Results: At least one rare protein-altering gene variant was identified in 19 patients, including
missense mutations in new candidate genes, namely SMC1 and REC8 (involved in the cohesin
complex) and LHX8, a gene encoding a transcription factor. Novel or recurrent deleterious mutations
were also detected in the known POI candidate genes NOBOX, FOXL2, SOHLH1, FIGLA, GDF9,
BMP15, and GALT. Seven patients harbor mutations in two loci, and this digenicity seems to
influence the age of symptom onset.
Conclusions: Genetic anomalies in women with POI are more frequent than previously believed.
Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to
a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic
effect of several mutations may underlie the POI phenotype. (J Clin Endocrinol Metab 101:
4541–4550, 2016)