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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Primary hyperoxaluria type 2 (PH2), caused by deficiency of the enzyme glyoxylate reductase/hydroxypyruvate reductase (GR/HPR), is characterized by recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis/urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), and end-stage renal disease (ESRD). After ESRD, oxalosis (widespread tissue deposition of calcium oxalate) usually develops. Symptom onset is typically in childhood.
Diagnosis/testing. Diagnosis relies on detection of increased urinary excretion of oxalate and commonly L-glycerate (although cases without L-glyceric aciduria have been reported), and either assay of glyoxylate reductase (GR) enzyme activity from liver biopsy or molecular genetic testing of GRHPR, the only gene associated with PH2.
Management. Treatment of manifestations: reduction of urinary calcium oxalate supersaturation through adequate daily fluid intake and treatment with inhibitors of calcium oxalate crystallization (orthophosphate, potassium citrate, and magnesium); temporary intensive dialysis for ESRD, followed by transplantation. Surveillance: assessment quarterly of renal function, blood pressure, and hematocrit; assessment of renal stone burden every six to 12 months by urinary tract imaging (renal ultrasound or CT); assessment of skin, bone, eye, and thyroid involvement annually after progression to ESRD. Agents/circumstances to avoid: dehydration. Ascorbate (vitamin C) ingestion and foods rich in oxalate (chocolate, rhubarb, and starfruit) may cause additional minimal increase in urinary oxalate levels in select individuals; excess should be discouraged. Testing of relatives at risk: For asymptomatic at-risk relatives offer urine analysis and, if indicated by the results of urine analysis, molecular genetic testing (if the disease-causing mutations in the family are known) so that early diagnosis can inform treatment.
Genetic counseling. PH2 is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.
Primary hyperoxaluria type 2 (PH2) is caused by deficiency of the enzyme glyoxylate reductase/hydroxypyruvate reductase (GR/HPR).
While clinical features (urinary tract symptoms or findings such as renal colic, kidney failure, urinary tract infection, hematuria, and/or obstruction of the urinary tract) may overlap with other causes of kidney stone formation, a clinical diagnosis of PH2 should be suspected if significant hyperoxaluria and coincident L-glyceric aciduria are present (see Testing).
Biochemical testing. For laboratories offering biochemical testing see
.
Urinary oxalate. Urinary oxalate can be measured either in a random or 24-hour collection of urine (designated 24h). Note: Because random ratios are subject to prandial variability, a timed collection is preferable if it can be obtained.
Urinary oxalate excretion in PH2 is typically greater than 0.7mmol/1.73m2/24h [Milliner 2005] although lesser increases may be observed.
Normal urinary oxalate excretion is less than 0.46 mmol/1.73m2/24h
Urinary L-glycerate. Although the presence of L-glycerate in the urine is regarded as pathognomonic for PH2 and the majority of affected individuals exhibit L-glyceric aciduria (8/8 in the series of Chlebeck et al [1994]), exceptions are reported [Rumsby et al 2001].
Kidney stone analysis. Kidney stones containing 100% calcium oxalate are supportive, but not diagnostic, of PH2.
Plasma oxalate. After the onset of renal failure, measurement of plasma oxalate concentration may be helpful. In contrast to plasma oxalate concentrations in persons with renal failure from other causes, plasma oxalate concentrations in individuals with primary hyperoxaluria with glomerular filtration rate lower than 20 mL/min/1.73m2 often exceed 50 μmol/L.
Glyoxylate reductase (GR) enzyme activity. Definitive diagnosis of PH2 requires measurement of glyoxylate reductase enzyme activity in a liver biopsy [Giafi & Rumsby 1998] or molecular genetic testing of GRHPR (see Molecular Genetic Testing).
Note: The enzyme has also been shown to be expressed in leukocytes [Knight et al 2006]; however, because of questions about the expression of the gene in leukocytes, measurement of enzyme activity in liver biopsy rather than leukocytes is recommended for diagnosis [Author observation].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. GRHPR (also known as GLXR), encoding glyoxylate reductase/ hydroxypyruvate reductase, is the only gene known to be associated with primary hyperoxaluria type 2.
Clinical testing
Sequence analysis. A two-tiered approach can be used:
Tier 1. Sequence analysis of exon 2 and exon 4 to detect the two commonly occurring mutations:
c.103delG in exon 2, which accounts for approximately 37% mutant alleles [Cregeen et al 2003]. It is possible to make a diagnosis (i.e., two mutations detected) in approximately 33% of individuals with liver biopsy-proven PH2 by testing for this mutation only [Rumsby et al 2004]. To date, this mutation has mainly been restricted to Caucasians.
c.403_405+2 delAAGT in exon 4, a four-base pair deletion, accounts for approximately 16% of disease alleles from individuals of predominantly Asian origin [Rumsby, unpublished observations].
Tier 2. Full gene sequencing. PCR amplification of genomic DNA with sequencing of individual exons and intron-exon boundaries has identified to date a total of 15 mutations [Cramer et al 1999, Webster et al 2000, Cregeen et al 2003, Booth et al 2006, Takayama et al 2007].
Linkage analysis. Closely linked microsatellite markers have been identified for GRHPR [Webster et al 2000, Johnson et al 2002] including one in intron 8 [Cregeen et al 2003]. These markers have been useful for the exclusion of disease in other family members (e.g., asymptomatic young sibs of an affected individual) and for the identification of carriers when the causative mutations of the affected individual have not been identified [Johnson et al 2002]; in both instances linkage results were confirmed subsequently by identification of the causative mutation [Rumsby 2005].
Table 1 summarizes molecular genetic testing for this disorder.
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| GRHPR | Sequence analysis | Sequence variants | >95% | Clinical
|
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To confirm/establish the diagnosis in a proband. An evidence-based guideline for the diagnosis of the primary hyperoxaluria type 1 (PH1) and primary hyperoxaluria type 2 (PH2) has been developed [Milliner 2005]. Because PH1 is more common than PH2, testing is first focused on the diagnosis of PH1 unless additional information (e.g., elevated urinary L-glycerate) suggests diagnosis of PH2.
In an individual with persistently elevated urinary oxalate (>0.7 mmol/1.73 m2/24h) and either:
Normal renal function, no excessive dietary oxalate intake, and no gastrointestinal disease or
Renal failure with an elevated plasma oxalate concentration (>20 μmol/L)
the following investigations are recommended:
Sequence analysis of exons 2 and 4 to look for the common mutations c.103delG and c.403_405+2 delAAGT
If two known mutations are found, a diagnosis of PH2 is made.
If only one mutation is found, perform sequence analysis of the rest of the gene to look for a second sequence variant.
If only one mutation is found after sequencing the whole gene, perform a liver biopsy to measure glyoxylate reductase enzyme activity to confirm or exclude a diagnosis of PH2.
Carrier testing for at-risk relatives requires either prior identification of the disease-causing mutations in the family or, if the mutations are not known, linkage analysis once the diagnosis of PH2 is certain in the proband.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutations in the family.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
No other phenotypes are known to be associated with mutations in GRHPR.
The age of onset of primary hyperoxaluria type 2 (PH2) is typically in childhood [Milliner et al 2001, Johnson et al 2002], with those diagnosed in later life often relating symptoms from childhood [Rumsby et al 2001, Takayama et al 2007]. As in PH1, establishing the diagnosis is often delayed, sometimes even for years.
Presenting symptoms are typically those associated with the presence of renal stones including hematuria, renal colic, or obstruction of the urinary tract [Johnson et al 2002]. Affected individuals may also present with nephrocalcinosis or end-stage renal disease (ESRD).
The majority of individuals have renal stones composed of calcium oxalate [Milliner et al 2001, Johnson et al 2002].
Nephrocalcinosis, observed on ultrasound examination, abdominal x-ray, or CT examination, is a much less common finding in PH2 than in PH1, having been described in one individual [Kemper & Muller Wiefel 1996].
The disease can progress to ESRD although this outcome appears to be later in PH2 than in PH1, in which 50% of affected individuals have ESRD by age 25 years [Leumann & Hoppe 2001].
Once ESRD occurs, deposition of oxalate can occur in organs other than kidney, including bone, bone marrow, retina, and myocardium [Wachter et al 2006, Wichmann et al 2003].
The low prevalence of PH2 does not allow genotype-phenotype correlations at the present time.
Primary hyperoxaluria type 2 was originally described as:
L-glyceric aciduria, referring to the excessive production of urinary glycerate
D-glycerate dehydrogenase deficiency, referring to the non-physiologic action of the enzyme in catalyzing the dehydrogenation of D-glycerate.
As the more important enzyme reactions appears to be that of glyoxylate reduction, the name glyoxylate reductase is now favored.
No data regarding the prevalence of PH2 exist. It is thought to be less common than primary hyperoxaluria type 1, which has a prevalence of approximately 1:1,000,000. However, there may be ascertainment bias in that individuals with early signs of PH2 may be misclassified clinically as having PH1 on the grounds of severity of symptoms and the correct diagnosis recognized only with appropriate testing.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Stone disease. For any individual presenting with symptoms related to renal stone disease it is essential to analyze the stone if at all possible as this can help to direct the clinician to a particular line of investigation. The stones in individuals with PH2 are calcium oxalate.
Urine should be analyzed for a stone risk profile which typically includes assessment of urine oxalate, calcium, magnesium, citrate, phosphate, and urate. Individuals with PH2 typically have urine oxalate excretions greater than 0.7 mmol/1.73 m2/day, in excess of levels usually seen in idiopathic calcium oxalate nephrolithiasis.
Other heritable disorders that present with early stone formation include PH1, Dent’s disease, renal tubular acidosis, cystinuria, xanthinuria, and 2,8 dihydroxyadeninuria.
Secondary hyperoxaluria. Disorders of the gastrointestinal tract leading to malabsorption have the potential to increase oxalate absorption and lead to hyperoxaluria; they can usually be excluded based upon history.
In addition, diets high in oxalate (for a listing of oxalate content of foods, see Holmes & Kennedy [2000] and Marcason [2006]) and low in calcium should be excluded and measurement of urine oxalate repeated on an oxalate-restricted diet.
Megadoses of vitamin C (4 g/day) have led to hyperoxaluria [Nasr et al 2006], as has ethylene glycol ingestion, either deliberate or accidental.
Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium salts that accumulate in the kidney and other organs. Individuals with PH1 are at risk for recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis/urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), or ESRD with a history of renal stones or oxalosis [Danpure 2001]. Although the hyperoxaluria is present from birth, and most individuals present in childhood or adolescence, age at symptom onset ranges from infancy to adulthood. Approximately 10% of affected individuals present before age four to six months with severe disease including nephrocalcinosis; 80%-90% present in late childhood or early adolescence with symptomatic nephrolithiasis; and fewer than 10% present in adulthood with recurrent renal stones. Untreated PH1 often progresses to nephrolithiasis/nephrocalcinosis, decline in renal function, oxalosis (widespread tissue deposition of calcium oxalate), and death from ESRD. Diagnosis relies on: (1) either (a) detection of increased urinary oxalate excretion (or elevated oxalate:creatinine ratio) or (b) in the setting of moderate to advanced renal failure, increased plasma oxalate concentration; and (2) deficiency of AGT catalytic activity from liver biopsy or molecular genetic testing of AGXT, the only gene known to be associated with PH1. Inheritance is autosomal recessive.
End-stage renal disease (ESRD). For persons presenting in ESRD, reliable measurement of urine oxalate excretion is not possible. While plasma oxalate elevations ranging up to 40 μmol/L may be detected with any form of ESRD, plasma oxalate concentrations exceeding 50 μmol/L are suggestive of primary hyperoxaluria. While PH1 and PH2 are a rare cause of ESRD in adults, it can account for 0.7-1.6% of ESRD in children. In a native kidney or renal allograft biopsy, PH should be considered if birefringent crystals are seen under polarized light. Although the measurement of plasma L-glycerate can identify individuals with PH2 who are in ESRD, such testing is not routinely available. Definitive diagnosis requires analysis of relevant enzymes in a liver biopsy or molecular genetic testing.
To establish the extent of disease in an individual diagnosed with primary hyperoxaluria type 2 (PH2), the following evaluations are recommended [Leumann & Hoppe 2001]:
Assessment of renal function
If moderate to advanced ESRD is present, assessment of systemic oxalate deposition in tissue and bone:
Bone X-rays to look for radiodense metaphyseal bands
Ophthalmic examination of the retina to look for oxalate crystals
Evaluation of cardiac function by echocardiography
Reduction of calcium oxalate supersaturation. As with PH1, conservative therapy is applied with the aim of minimizing oxalate-related renal injury and preserving renal function. Treatment of persons with preserved renal function, reviewed by Leumann & Hoppe [2001], essentially aims to improve oxalate solubility as follows:
Adequate fluid intake (>2.5L/m2 surface area/day)
Urinary inhibitors of calcium oxalate crystallization:
Orthophosphate treatment (20-60 mg/kg body weight/day) [Leumann & Hoppe 2001] (20-60 mg/kg body weight/day)
Potassium citrate (0.1-0.15 g/kg body weight/day) [Leumann & Hoppe 2001]
Magnesium supplements (200-300 mg/day in divided doses) [Watts 1994]
Dialysis. Because the plasma oxalate concentration begins to rise when the renal clearance is less than 40 mL/min/1.73m2, early initiation of dialysis or preemptive kidney-only transplantation is preferred. For patients in ESRD, intensive (daily) dialysis is required to maximize oxalate removal. As in PH1, the longer the individual with PH2 is on dialysis the more likely systemic oxalate deposition will occur.
Organ transplantation. Kidney transplantation alone has been used in PH2 with varying success. Careful management in the postoperative period, with attention to brisk urine output and use of calcium oxalate urinary inhibitors, minimizes the risk of allograft loss as a result of oxalate deposition.
To date, liver-kidney transplantation has not been used in PH2; however, as there is more enzyme present in the liver than in other tissues [Cregeen et al 2003], this strategy may have some merit.
Pharmacologic doses of pyridoxine are used as a treatment in PH1 because of its role as cofactor for the defective enzyme. Its role in PH2 is unproven, but doses in the range of that found in typical multivitamin tablets have been used in an attempt to boost transaminases (including alanine:glyoxylate aminotransferase) with glyoxylate metabolizing activity.
The main preventative treatment is to maintain adequate hydration status and to enhance calcium oxalate solubility with exogenous citrate and neutral phosphates as described in Treatment of Manifestations.
Frequency of testing depends on the center; however, as a guide, the following are recommended:
Quarterly. Assessment of renal function, blood pressure, and hematocrit
Six monthly to annually. Renal imaging (ultrasound or CT examination) to assess renal stone burden*
Annually. Examination for involvement of the skin, bone, eye, or thyroid*
For pregnant women with PH2, close monitoring by both an obstetrician and nephrologist because of the increased risk of developing nephrolithiasis during pregnancy or after delivery
* Investigations should likely occur more often in newly diagnosed symptomatic individuals or in children younger than age two to three years.
The following should be avoided:
Dehydration
Excessive ascorbate (i.e., vitamin C; >1000 mg/day)
Foods rich in oxalate (chocolate, rhubarb, spinach, and starfruit in particular)
In order to delay disease onset in asymptomatic relatives, it is prudent to screen at-risk family members before symptoms occur by measuring urinary oxalate excretion or by molecular genetic testing, if the disease-causing mutations in the family are known. Molecular genetic testing tends to be more reliable as urine oxalate output can be variable in childhood.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Treatment with Oxalobacter formigenes is currently undergoing clinical trials in patients with hyperoxaluria and may provide an additional form of treatment for PH1 and PH2 [Hoppe et al 2006] by inducing oxalate excretion into the gut [Hatch & Freel 2003].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Primary hyperoxaluria type 2 (PH2) is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with PH2 are obligate heterozygotes (carriers) for a disease-causing mutation.
Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is possible once the mutations have been identified in the family.
See Testing Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Family planning
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for conditions which, like PH2, do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate. Side effects of renal and/or liver transplantation and scarcity of suitable organs for transplantation may be a consideration for parents who already have one affected child.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| GRHPR | 9cen | Glyoxylate reductase/hydroxypyruvate reductase |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| GRHPR | 9380 (MIM No. 604296) | GRHPR |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
Normal allelic variants. The GRHPR gene (also known as GLXR) is composed of nine exons spanning approximately 9 kb; the entire gene can be found within a single contig, NT_008413.17. The mRNA [Cramer et al 1999, Rumsby & Cregeen 1999] encodes a protein of 328 amino acids. Two polymorphic variants, a dinucleotide repeat in intron 8 (c.866-10_25(CT)n) and a single nucleotide variant c. 579A>G in exon 6 have been described [Cregeen et al 2003].
Pathologic allelic variants. A number of mutations have been described in the GRHPR gene [Cramer et al 1999, Webster et al 2000, Lam et al 2001, Cregeen et al 2003, Booth et al 2006, Takayama et al 2007]. PCR amplification of genomic DNA with sequencing of individual exons and intron-exon boundaries has identified a total of 15 mutations to date [Cramer et al 1999, Webster et al 2000, Cregeen et al 2003, Takayama et al 2007].
Just over 50% of mutations in this gene are minor deletions, the rest are point mutations affecting a splice site or leading to a missense change [Cramer et al 1999, Webster et al 2000, Cregeen et al 2003, Takayama et al 2007]. To date, c.103delG has been found primarily in Caucasians and c.403_405+2delAAGT in Asian individuals.
Tissue-specific differences in expression of mutations and polymorphisms has been reported; until this issue is understood, it is recommended that expression studies use only GRHPR cDNA derived from liver [Bhat et al 2005].
| Class of Variant Allele | DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence |
|---|---|---|---|
| Normal | c.579A>G | None | NM_012203.1NP_036335.1NT_008413.17 |
| c.866-10_25(CT)n | None | ||
| Pathologic | c.103delG | p.Asp35ThrfsX11 | |
| c.403_405+2delAAGT | Missplicing |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
Normal gene product. The normal protein is a homodimer. The protein has a large coenzyme-binding domain (residues 107-298) and a smaller substrate-binding domain (5-106 and 299-328) [Booth et al 2006]. A prominent extended helical and loop region wraps around the other subunit (dimerization loop, residues 123-149). The apex of this loop contains a tryptophan residue at position 141 and the residue from one subunit is projected into the active site of the other subunit and contributes to substrate specificity [Booth et al 2006]. The protein is found primarily in the cytosol although some immunoreactivity has been found within the mitochondria of cells [Knight & Holmes 2005, Behnam et al 2006]. The significance of this finding in vivo is unknown.
Abnormal gene product. All the missense mutations described to date result in proteins with no catalytic activity [Webster et al 2000, Cregeen et al 2003]. Other mutations that affect splicing or create frameshifts or nonsense mutations would also fail to yield a functional product. All mutations are, therefore, essentially null alleles.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Hyperoxaluria, primary
Oxalosis and Hyperoxaluria Foundation
201 East 19th Street Suite 12E
New York NY 10003
Phone: 800-OHF-8699 (800-643-8699); 212-777-0470
Fax: 212-777-0471
Email: execdirector@ohf.org
www.ohf.org
Children Living with Inherited Metabolic Diseases (CLIMB)
Climb Building
176 Nantwich Road
Crewe CW2 6BG
United Kingdom
Phone: 0800-652-3181 (toll free); 0845-241-2172
Fax: 0845-241-2174
Email: info.svcs@climb.org.uk
www.climb.org.uk
International Registry for Hereditary Calcium Stone Diseases
Phone: 800-270-4637
Email: hyperoxaluriacenter@mayo.edu
Hereditary Calcium Stone Registry
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
2 December 2008 (me) Review posted live
9 September 2008 (gr) Original submission
