Summary
Clinical 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 kidney disease (ESKD). After ESKD, oxalosis (widespread tissue deposition of calcium oxalate) usually develops. Symptom onset is typically in childhood.
Diagnosis/testing.
The diagnosis of PH2 is established in a proband by identification of biallelic pathogenic variants in GRHPR by molecular genetic testing. If no pathogenic variants or only one pathogenic variant is identified by molecular genetic testing, identification of reduced glyoxylate reductase enzyme activity on liver biopsy can establish the diagnosis of 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 ESKD, followed by transplantation.
Surveillance: Biannual assessment of kidney function, urinalysis with measurements of urine oxalate excretion (using 24-hour collection if easy to facilitate or spot urine oxalate to creatinine ratio), and calcium oxalate saturation if available, blood pressure, and full blood count including hematocrit; assessment of kidney stone burden every six to 12 months by urinary tract imaging (renal ultrasound or CT); assessment of cardiac, skin, bone, joint, eye, thyroid, and hematologic involvement annually after progression to ESKD.
Agents/circumstances to avoid: Dehydration. Ascorbate (vitamin C) ingestion and foods rich in oxalate (chocolate, rhubarb, and star fruit) may cause additional minimal increase in urinary oxalate levels in select individuals; excess should be discouraged; high salt (sodium) diet should be discouraged; excessive stone interventions with extracorporal shock wave lithotripsy.
Evaluation 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 pathogenic variants 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 a pregnancy at increased risk are possible if the pathogenic variants in the family are known.
Diagnosis
Suggestive Findings
Primary hyperoxaluria type 2 (PH2) should be suspected in individuals with the following clinical and laboratory features.
Clinical features
Symptoms of nephrolithiasis (e.g., hematuria, renal colic, obstruction of the urinary tract)
Frequent recurrent nephrolithiasis
Nephrocalcinosis
End-stage kidney disease with a history of nephrolithiasis
Laboratory features
Kidney stone analysis. Kidney stones containing predominantly calcium oxalate
Increased urinary oxalate, typically greater than 0.7 mmol/1.73 m2/24h (normal <0.46 mmol/1.73 m2/24h). A 24-hour collection in acid is preferable to a random sample.
Increased urinary L-glycerate. This analyte may be detected on an organic acid screen, but there is considerable variability between methods and a specific method for glycerate is preferable.
Increased plasma oxalate. After the onset of kidney failure, measurement of plasma oxalate concentration may be helpful. In contrast to the elevated plasma oxalate concentrations in persons with kidney failure from other causes, plasma oxalate concentrations in individuals with primary hyperoxaluria with glomerular filtration rate lower than 20 mL/min/1.73 m2 often exceed 50 μmol/L.
Establishing the Diagnosis
The diagnosis of PH2 is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in GRHPR by molecular genetic testing (see Table 1). If no pathogenic variants or only one pathogenic variant is identified by molecular genetic testing, identification of reduced glyoxylate reductase enzyme activity on a liver biopsy can establish the diagnosis of PH2.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic GRHPR variants of uncertain significance (or of one known GRHPR pathogenic variant and one GRHPR variant of uncertain significance) does not establish or rule out the diagnosis.
Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:
Table 1.
Molecular Genetic Testing Used in Primary Hyperoxaluria Type 2
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| Gene 1 | Method | Proportion of Pathogenic Variants 2 Identified by Method |
|---|
|
GRHPR
| Sequence analysis 3 | >99% 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
- 1.
- 2.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Author, personal communication
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Assay of glyoxylate reductase enzyme activity
The enzyme is primarily expressed in the liver [
Cregeen et al 2003] and can be analyzed in liver tissue using the method described by
Giafi and Rumsby [1998]. A needle biopsy (~20 mg of tissue) is required and the sample must be frozen immediately and shipped frozen to the laboratory.
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 [
Bhat et al 2005] and the low activity, measurement of enzyme activity in liver biopsy rather than leukocytes is recommended for diagnosis [Author, personal observation].
Clinical Characteristics
Clinical Description
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, diagnosis is often delayed, sometimes even for years.
Presenting symptoms are typically those associated with the presence of kidney 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 kidney disease (ESKD).
The majority of individuals have kidney stones composed of calcium oxalate [Milliner et al 2001, Johnson et al 2002].
Nephrocalcinosis, observed on ultrasound examination, abdominal radiograph, or CT examination, is a much less common finding in PH2 than in PH1.
The disease can progress to ESKD although this outcome appears to be later in PH2 than in PH1, in which 50% of affected individuals have ESKD by age 25 years [Leumann & Hoppe 2001]. In a recent review of data collected through the OxalEurope Registry, of 83 individuals with PH2, 20% developed ESKD at follow up [S Hulton, personal communication].
Oxalosis. Once ESKD occurs, deposition of oxalate can occur in organs other than kidney, including bone, bone marrow, joints, retina, and myocardium [Wichmann et al 2003, Wachter et al 2006] along with calcified nodules on the fingers [Yamanouchi et al 2016].
Oxalate deposition in bone results in radiograph findings of transverse translucent symmetric bands with fixed sclerotic margins at the end of long bones followed by cystic rarefaction of the bones. Osteodystrophy causes bone pain and multiple pathologic fractures occur in advanced disease. Involvement of the bone marrow can result in anemia refractory to erythropoietin-stimulating agents.
Additional clinical manifestations of oxalosis may include visual disturbance due to retinopathy and/or maculopathy, cardiac conduction disturbances such as heart block, cardiomyopathy, and synovitis secondary to oxalate deposition in the joints. Vascular involvement can lead to ischemia, most often manifest as non-healing cutaneous ulcers. Dental complications include periodontal disease. Hypothyroidism is also reported.
Genotype-Phenotype Correlations
The low prevalence of PH2 does not allow genotype-phenotype correlations at the present time.
Nomenclature
Primary hyperoxaluria type 2 was originally described as:
L-glyceric aciduria, referring to the excessive production of urinary L-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 reaction appears to be that of glyoxylate reduction, the name glyoxylate reductase is now favored.
Prevalence
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.
Differential Diagnosis
Primary hyperoxaluria type 1
(PH1) is the most common form of inherited hyperoxaluria, accounting for approximately 80% of cases. It 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 ESKD with a history of kidney stones or oxalosis. 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 15% of affected individuals present before age four to six months with severe disease including nephrocalcinosis; 55% present in childhood or early adolescence with symptomatic nephrolithiasis; and the remainder present in adulthood with recurrent kidney stones. Untreated PH1 often progresses to nephrolithiasis/nephrocalcinosis, decline in kidney function, systemic oxalosis (widespread tissue deposition of calcium oxalate), and death from ESKD. 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 kidney 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.
Primary hyperoxaluria type 3
(PH3) has a phenotype similar to that of PH1 and PH2 and accounts for approximately 10% of cases of primary hyperoxaluria [Cochat & Rumsby 2013]. A provisional biochemical diagnosis can be made by the finding of elevated 4-hydroxy-2-oxoglutarate and 2,4-dihydroxyglutarate in urine followed by confirmation with sequence analysis of HOGA1. Pathogenic variants in HOGA1 result in deficiency of mitochondrial 4-hydroxy-2-oxoglutarate aldolase, an enzyme that catalyzes one of the steps in the metabolism of hydroxyproline. The hyperoxaluria in individuals with PH3 arises from breakdown of the substrate for the enzyme rather than excessive production of glyoxylate. Inheritance is autosomal recessive.
Other hereditable causes of kidney stones. Other heritable disorders that present with early stone formation include Dent disease, renal tubular acidosis, cystinuria (OMIM 220100), xanthinuria (OMIM 278300, 603592), and adenine phosphoribosyltransferase deficiency. In individuals presenting with symptoms related to kidney stone disease it is essential to analyze the stone if possible as this can help to direct the clinician to a particular line of investigation. Urine should be analyzed for a stone risk profile that typically includes assessment of urine volume, oxalate, calcium, magnesium, citrate, phosphate, sodium, and urate.
End-stage kidney disease (ESKD). For persons presenting in ESKD, reliable measurement of urine oxalate excretion is not possible. Plasma oxalate elevations ranging up to 40 μmol/L may be detected with any form of ESKD; plasma oxalate concentrations exceeding 50 μmol/L are suggestive of primary hyperoxaluria. While PH1 and PH2 are a rare cause of ESKD in adults, PH can account for 0.7%-1.6% of ESKD in children. In a native kidney or kidney 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 ESKD, such testing is not routinely available. Definitive diagnosis requires molecular genetic testing or analysis of relevant enzymes in a liver biopsy.
Enteric hyperoxaluria. Disorders of the gastrointestinal tract leading to malabsorption (e.g., celiac disease, Crohn disease, pancreatitis, short bowel syndrome) have the potential to increase oxalate absorption and lead to hyperoxaluria; they can usually be excluded based on history. Gastric bypass procedures have been associated with increased oxalate absorption, high levels of hyperoxaluria, and increased risk of kidney stone formation [Asplin & Coe 2007, Kleinman 2007, Duffey et al 2008, Lieske et al 2008]. Urinary risk factors for stones such as hyperoxaluria occur more commonly in individuals with Roux-en-Y gastric bypass than gastric banding [Semins et al 2010, Kumar et al 2011, Tasca 2011].
Dietary hyperoxaluria. Excess intake of foods high in oxalate including chocolate, cocoa, leafy greens (especially rhubarb and spinach), black tea, nuts, peanut butter, or starfruit may increase urinary concentration of oxalate. Between 24% and 53% of urinary oxalate is attributable to oxalate from the diet [Holmes & Assimos 2004]. Therapy consists of dietary oxalate restriction and use of calcium carbonate or calcium citrate at meal times to bind dietary oxalate [Penniston & Nakada 2009].
Megadoses of vitamin C (4 g/day) have led to hyperoxaluria [Nasr et al 2006], as has (deliberate or accidental) ingestion of ethylene glycol.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with primary hyperoxaluria type 2 (PH2), the following evaluations, originally outlined for PH1, are recommended if they have not already been completed [Cochat et al 2012]:
Assessment of kidney function
If moderate to advanced ESKD is present, assessment of systemic oxalate deposition in tissue and bone:
Bone radiographs to look for radiodense metaphyseal bands followed by cystic rarefaction of bones
Ophthalmic examination of the retina to look for oxalate crystals
Evaluation of cardiac function by echocardiography and EKG
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Management follows general guidance for that of kidney stones: to relieve obstruction, and to manage symptoms of renal impairment as they arise.
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 Cochat et al [2012], essentially aims to improve oxalate solubility as follows:
Dialysis
Because the plasma oxalate concentration begins to rise when the renal clearance is less than 40 mL/min/1.73 m2, early initiation of dialysis or preemptive kidney-only transplantation is preferred.
Oxalate clearance on hemodialysis is greater than on peritoneal dialysis (120 mL/min on hemodialysis vs 7 mL/min on peritoneal dialysis): standard hemodialysis programs will result in clearance of oxalate of 6-9 mmol/1.73 m2/week, which is equivalent to two to three days of endogenous production of oxalate. Thus a combination of modalities, with intermittent daily hemodialysis together with overnight peritoneal dialysis, or intense home hemodialysis, enhances the overall clearance of oxalate and attempts to reduce the rebound that occurs after hemodialysis. These combination therapies, with the use of high flux dialyzers or long episodes of hemofiltration, have all been advocated to improve oxalate removal [Hoppe et al 1996, Illies et al 2006].
For individuals in ESKD, 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. As it is not unusual for such transplants to fail in individuals with PH2 and as there is more enzyme present in the liver than in other tissues [Cregeen et al 2003], combined liver-kidney transplant may have some merit.
To date, there is just one published report of a successful liver-kidney transplantation in an individual with PH2 with a previously failed kidney allograft [Dhondup et al 2018]. Urine glycerate and oxalate and plasma oxalate all normalized within one month post transplant and remained normal for the 13-month follow up.
Other
Pharmacologic doses of pyridoxine are used as a treatment in individuals with PH1 because of its role as a cofactor for the defective enzyme. There is no supportive evidence for the use of pyridoxine in individuals with PH2.
Prevention of Primary Manifestations
The main preventive 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.
Surveillance
Frequency of recommended screening can vary; however, as a guide, the following are recommended.
Individuals with preserved renal function (i.e., measured or estimated GFR ≥60 mL/min/1.73 m2) require the following to evaluate/ensure treatment efficacy:
Biannually. Assessment of renal function, urinalysis with measurements of urine oxalate excretion using 24-hour collection if easy to facilitate; or spot urine oxalate-to-creatinine ratio, and calcium oxalate saturation if available, blood pressure, and full blood count including hematocrit. The presence of blood in the urine may indicate stones, but protein in an early morning sample necessitates review of renal function as it may herald a decline in GRF.
Biannually to annually. Renal imaging (ultrasound or CT examination) to assess kidney stone burden as appropriate. Note: Annual scans are appropriate if no stones or nephrocalcinosis are visualized.
Individuals with a GFR <60 mL/min/1.73 m2 should have the above evaluations performed quarterly, as well as the following testing annually to evaluate for involvement of other organ systems apart from the renal tract.
Bone. Radiographs to evaluate for the development of transverse translucent symmetric bands with fixed sclerotic margins at the end of long bones, cystic rarefaction of bones, and pathologic fractures. DXA (dual-energy x-ray absorptiometry) scanning may be considered every five years. MRI or CT scanning of bones may provide further information but are not routinely recommended at present.
Hematology. Full blood count with hematocrit for anemia; a bone marrow aspirate may rarely be required to determine if oxalate crystals in the bone marrow are contributing to an erythropoietin resistant anemia.
Eye. Ophthalmology examination with fundoscopy to evaluate for retinopathy and maculopathy
Cardiac. Electrocardiogram for cardiac conduction defects and echocardiogram to evaluate contractility if appropriate
Skin. Clinical examination for subungual deposits of oxalate and cutaneous ulcers as evidence of vasculopathy
Joints. Clinical examination for evidence of synovitis; arthroscopy may be considered on an individual basis.
Teeth. Dental examination for periodontal disease
Thyroid. Thyroid function tests including TSH and free T4 for hypothyroidism
Plasma oxalate. Measure every four to six months until GFR falls below 15 mL/min/1.73 m2 when levels will be noted to rise in keeping with renal impairment and may become more difficult to interpret. While on dialysis, measure plasma oxalate monthly to inform changes in dialysis prescription.
Agents/Circumstances to Avoid
The following should be avoided:
Dehydration
Excessive ascorbate (i.e. vitamin C; >1000 mg/day)
Foods rich in oxalate (chocolate, rhubarb, spinach, and star fruit in particular)
High salt (sodium) diet should be discouraged.
Excessive stone interventions with extracorporal shock wave lithotripsy
Evaluation of Relatives at Risk
In order to delay disease onset in asymptomatic relatives, it is prudent to evaluate at-risk family members before symptoms occur. Evaluations can include:
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.
Pregnancy Management
For pregnant women with PH2, close monitoring by both an obstetrician and nephrologist is indicated because of the increased risk of decline in kidney function together with developing nephrolithiasis during pregnancy or after delivery.
See MotherToBaby for further information on medication use during pregnancy.
Therapies Under Investigation
Oxalobacter formigenes treatment did not demonstrate significant effect in reducing oxalate via gut excretion in individuals with PH1 but continues to undergo clinical trials in individuals with hyperoxaluria and impaired kidney function [Hoppe et al 2017].
Other proposed trials include the use of inhibitors of glycolate oxidase (ALN-GO1) to reduce the amount of glyoxylate produced, although this treatment would be mainly relevant to treatment of individuals with PH1.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Primary hyperoxaluria type 2 (PH2) is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
The parents of an affected individual are obligate heterozygotes (i.e., carriers of GRHPR pathogenic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
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.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Offspring of a proband. The offspring of an individual with PH2 are obligate heterozygotes (carriers) for a pathogenic variant in GRHPR.
Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a GRHPR pathogenic variant.
Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the GRHPR pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Testing
Once the GRPHR pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. Complications relating to kidney and/or liver transplantation and scarcity of suitable organs for transplantation may be a consideration for parents who already have one affected child.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
MedlinePlus
Oxalosis & Hyperoxaluria Foundation
Phone: 212-777-0470
Email: info@ohf.org
Kidney Health Initiative Patient and Family Partnership Council (KHI PFPC)
Metabolic Support UK
United Kingdom
Phone: 0845 241 2173
OxalEurope Registry (OER)
Rare Kidney Stone Consortium Registry
Phone: 800-270-4637 (toll-free)
Email: hyperoxaluriacenter@mayo.edu
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Primary Hyperoxaluria Type 2: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure.
GRHPR (previously known as GLXR) is composed of nine exons spanning approximately 9 kb. The transcript NM_012203.1 encodes a protein of 328 amino acids (NP_036335.1). For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Information on specific pathogenic variants is available in the HGMD, ClinVar, and locus-specific databases in Table A.
Table 2.
Selected GRHPR Pathogenic Variants
View in own window
| DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
|---|
| c.103delG | p.Asp35ThrfsTer11 |
NM_012203.1
NP_036335.1
|
| c.403_404+2delAAGT | Missplicing |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
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 pathogenic missense variants described to date result in proteins with no catalytic activity [Webster et al 2000, Cregeen et al 2003]. Other variants that affect splicing or create frameshifts or nonsense variants would also fail to yield a functional product. All pathogenic variants are, therefore, essentially null alleles.
Chapter Notes
Revision History
21 December 2017 (sw) Comprehensive update posted live
5 May 2011 (me) Comprehensive update posed live
2 December 2008 (me) Review posted live
9 September 2008 (gr) Original submission
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