Figure 1. Hepatic biopsy showing vascular obliteration, peri-venular fibrosis, zone 3 fibrosis and hepatocyte dropout from a girl who presented at age five months with hepatomegaly and ascites (Picro-Mallory stain 100x)
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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. Hepatic veno-occlusive disease with immunodeficiency (VODI) is characterized by primary immunodeficiency and terminal hepatic lobular vascular occlusion and hepatic fibrosis manifest as hepatomegaly and/or hepatic failure. Onset is before age 12 months. The immunodeficiency comprises severe hypogammaglobulinemia, clinical evidence of T cell immunodeficiency with normal numbers of circulating T cells, absent lymph node germinal centers, and absent tissue plasma cells. Bacterial and opportunistic infections including Pneumocystis jerovici infection, mucocutaneous candidiasis, and enteroviral or cytomegalovirus infections occur. VODI is associated with a 90% mortality overall and 100% mortality if unrecognized and untreated with intravenous immunoglobulin (IVIG) and Pneumocystis jerovici prophylaxis.
Diagnosis/testing. Diagnosis is based on histologic examination of the liver (or hepatic ultrasonography and Doppler ultrasonography if hepatic biopsy is not possible), low serum concentrations of IgA, IgM, and IgG for age, normal lymphocyte numbers, normal CD4 and CD8 percentages, and molecular genetic testing. SP110 is the only gene known to be associated with VODI. Targeted mutation analysis for a panel of three mutations detected both mutations in all eight individuals with VODI tested to date. Sequence analysis is also clinically available.
Management. Treatment of manifestations: intravenous immunoglobulin (IVIg) and Pneumocystis jerovici prophylaxis as soon as the diagnosis of VODI is established; appropriate, prompt treatment of infections; consider HSCT and hepatic transplantation, but rate of complications may be high. Prevention of primary manifestations: IVIg and Pneumocystis jerovici prophylaxis. Surveillance: regular monitoring of hepatic function, platelet count, and hemoglobin level; broncho-alveolar lavage to diagnose Pneumocystis jerovici infection, viral cultures or lung function studies as needed. Agents/circumstances to avoid: cyclophosphamide and senecio alkaloids/bush teas (agents known to predispose to hVOD). Testing of relatives at risk: if both disease-causing mutations are known, molecular genetic testing of sibs of a proband who are younger than age 12 months.
Genetic counseling. VODI is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (carriers) and therefore carry one mutant allele. Heterozygotes are asymptomatic. 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. Prenatal diagnosis for pregnancies at increased risk is possible if both disease-causing alleles of an affected family member have been identified.
The clinical diagnostic criteria for hepatic veno-occlusive disease with immunodeficiency (VODI) syndrome include the following:
Clinical evidence of immunodeficiency with bacterial and opportunistic infections including Pneumocystis jerovici infection, mucocutaneous candidiasis, and enteroviral or cytomegalovirus infections
Hepatomegaly or evidence of hepatic failure not explained by other factors in the affected individual or a first degree relative
Onset before age 12 months
Family history consistent with autosomal recessive inheritance
Additional investigations that support the clinical diagnosis of VODI include the following:
Figure 1. Hepatic biopsy showing vascular obliteration, peri-venular fibrosis, zone 3 fibrosis and hepatocyte dropout from a girl who presented at age five months with hepatomegaly and ascites (Picro-Mallory stain 100x)
Figure 1)* Low serum concentrations of IgA, IgM, and IgG. Immunoglobulin levels are age-specific and laboratory-specific and so should be compared against appropriate local reference ranges.
Normal lymphocyte numbers and CD4 and CD8 percentages
Low intracellular cytokine production
Hepatic ultrasonography. Features consistent with hVOD may include hepatosplenomegaly, gallbladder wall thickening, increased portal vein diameter, reduced hepatic vein diameter, ascites, and re-canalization of the ligamentum teres.
Doppler ultrasound examination. Features consistent with hVOD may include reduced portal venous flow, flow in the para-umbilical vein, and increased resistance in the hepatic artery [Lassau et al 1997].
* If hepatic biopsy is contraindicated, hepatic ultrasonography and Doppler ultrasonography may provide supportive evidence of hVOD.
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. SP110 is the only gene known to be associated with VODI.
Clinical uses
Confirmatory diagnostic testing
Carrier testing
Prenatal diagnosis
Clinical testing
Targeted mutation analysis. SP110 mutations associated with VODI have been described in the following:
Exon 2: c.40delC (p.Q14SfsX25)
Exon 4: c.319_325dupGGTGCTT (p.S109WfsX5)
Exon 5: c.642delC (p.P214PfsX14)
Each of these pathogenic mutations causes a frameshift with consequent protein truncation. Targeted mutation analysis through sequencing of the coding regions of these exons is therefore the first step in diagnostic testing. Targeted mutation analysis of exons 2, 4, and 5 detected both mutations in 100% of the eight individuals with VODI evaluated to date [Roscioli et al 2006, Ruga et al 2006].
Sequence analysis. Molecular testing for SP110 sequence variants is available through sequencing of the entire coding region of 19 exons and an alternatively spliced exon 15 in the Sp110c isoform.
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Rate | Test Availability |
|---|---|---|---|
| Targeted mutation analysis | c.40delC, c.319_325dupGGTGCTT, c.642delC | 8/8 (100%) | Clinical
 |
| Sequence analysis | Other SP110 coding and intron-exon boundary mutations |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
The diagnosis of VODI is initially a clinical diagnosis and should be considered in children who present before age 12 months with hepatomegaly or hepatic failure.
Measure serum immunoglobulin concentrations
If serum concentration of immunoglobulins is low for age, hepatic imaging and/or hepatic biopsy (if not contraindicated) to confirm the presence of hVOD
Molecular genetic testing
No allelic Mendelian disorders for SP110 or contiguous gene disorders including the SP110 region associated with hVOD or immunodeficiency have been described.
Tosh et al (2006) reported transmission disequilibrium for alleles of SP110 in Mycobacterium tuberculosis infection in individuals of West African heritage. However, a replication study in a population derived from the same region did not identify an association between SP110 alleles and Mycobacterium tuberculosis infection [Thye et al 2006]. A well-designed and well-executed study by Szeszko et al (2006) failed to detect a significant association between alleles of SP110 and Mycobacterium tuberculosis infection in Russian Caucasians. It is notable that the three studies cited compare Mantoux-positive and Mantoux-negative individuals rather than disease progression in individuals known to be exposed to Mycobacterium tuberculosis.
Hepatic veno-occlusive disease (hVOD) with immunodeficiency (VODI) is a primary immunodeficiency associated with terminal hepatic lobular vascular occlusion and hepatic lobule zone 3 fibrosis.
The immunodeficiency is characterized by severe hypogammaglobulinemia, clinical evidence of T cell immunodeficiency with normal numbers of circulating T cells, absent lymph node germinal centers, and absent tissue plasma cells [Roscioli et al 2006]. The number of children known to have VODI secondary to SP110 mutations is small (Table 2 and Table 3) [Roscioli et al 2006, Ruga et al 2006].
All children in the cohort from Sydney, Australia presented prior to age six months, the majority with sequelae of the immunodeficiency either alone or concurrently with features of hVOD (see Table 2). Ninety percent of the children with VODI present ab initio either with hepatomegaly (83% with preceding infection) or hepatic failure (53% with preceding infection). Table 2 summarizes the clinical and immunologic features of 20 individuals with VODI.
| Clinical Feature | Number of Affected Individuals (%) | Comments |
|---|---|---|
| Hepatic failure at initial presentation | 12/20 (60%) | 7/12 post infection 1/12 post HSCT 1/12 post surgery 3/12 no obvious precipitant |
| Hepatomegaly at initial presentation | 6/20 (30%) | 3/6 Pneumocystis jerovici 1/6 enterovirus 1/6 disseminated CMV 2/6 hepatomegaly without hVOD |
| Pneumocystis jerovici infection | 12/20 (60%) | 7/12 proven, 5/12 suspected |
| Mucocutaneous candidiasis | 2/20 (10%) | |
| Death | 18/20 (90%) | |
| Recovery from initial hVOD | 4/20 (20%) | 1 completely well 1 chronic liver disease requiring hepatic transplantation 1 hVOD post HSCT 1 developmental disability, chronic aspiration |
| Neurologic abnormalities | 6/20 (30%) | 4/6 cerebral infarction 1/6 Toxoplasma? 1/6 porencephalic cyst |
| Panhypogammaglobulinemia | 18/18 (100%) | 1/18 loss of normal immunoglobulins at age 4 months; 1/18 low normal levels of IgA and IgM after commencing IVIG |
| Normal number of lymphocytes | 11/12 (92%) | |
| Normal B cell precursors | 12/12 (100%) | |
| Normal NK cells | 12/12 (100%) | |
| Decreased intracytoplasmic IFNγ, IL2, IL4, IL10 | 4/5 (80%) | Low levels at 4 hours, normal/increased levels at 48 hours |
| Decreased number of memory T and B cells | 3/4 (75%) | These cells were present in the individual with the exon 4 duplication |
Table modified from Roscioli et al (2006)
HSCT=hematopoetic stem cell transplantation
CMV= cytomegalic virus
IVIG= intravenous immunoglobulin
VODI is associated with a 90% mortality overall and 100% mortality if unrecognized and untreated with intravenous immunoglobulin (IVIG) and Pneumocystis jerovici prophylaxis [Roscioli et al 2006]. Should hVOD recovery occur, recurrence of hVOD appears to be prevented by continuation of intravenous immunoglobulin and pneumocystis prophylaxis. One child (Patient AII.1, Table 3) died following recurrence of hVOD after bone marrow transplantation at age six years.
Overall, 30% of children with VODI had neurologic involvement. In no case was veno-occlusive disease of the brain reported. One affected child (Patient BII.1, Table 3) had intellectual disability associated with a porencephalic cyst of uncertain origin; a second child in the same sibship and three others had multi-organ failure associated with extensive cerebral necrosis on post-mortem examination. Patient AII.1 (Table 3) experienced a cerebrovascular accident associated with a right-sided cerebral white matter lesion, presumed to be Toxoplasma gondii infection.
Table 3 outlines clinical features in individuals with a known SP110 mutation [Roscioli et al 2006].
| Patient | SP110 Mutation | Presentation | Serum Igs | Memory T/B Cells | T Cell Cytokines | Clinical Findings | Deceased? |
|---|---|---|---|---|---|---|---|
| AII.1 1 | c.642delC | Age 5 months: immunodeficiency, thrombocytopenia, hVOD | ↓ | — | — | Left hemiparesis 2 , recurrent hVOD with GVHD post HSCT | Yes |
| BII.1 1 | Age 7 months: immunodeficiency | ↓ | — | — | Chronic lung disease secondary to recurrent aspiration | Yes (age 19 years) | |
| BII.2 1 | Age 6 months: hepatosplenomegaly, ascites, hVOD | ↓ | ↓ | ↓ | Well | ||
| CII.1 1 | Age 4 months: hepatosplenomegaly, ascites, hVOD, thrombocytopenia, mucocutaneous candidiasis | ↓ | ↓ | ↓ | Chronic liver disease, portal hypertension post hepatic transplantation | ||
| DII.1 1 | Age 3 months: hepatosplenomegaly, ascites, hVOD | ↓ initially 3 | ↓ | ↓ | Hemophagocytic syndrome post hepatic transplantation | Yes | |
| G | Age 3 months: hepatosplenomegaly, ascites, hVOD | ↓ | ↓ | ↓ | Pulmonary hemorrhage, multi-organ failure | Yes | |
| EI.1 1 | c.40delC | Age 3 months: immunodeficiency, thrombocytopenia | ↓ | N/A | N/A | Enteroviral and Pneumocystis jerovici infection | Yes |
| F | c.319_325dup GGTGCTT | Age 11 months: disseminated CMV infection, rotavirus gastroenteritis, vulvar abscesses, hVOD | ↓initially | Normal | Normal | Recovering from hVOD |
Modified from Roscioli et al (2006)
GVHD = graft vs host disease
HSCT = hematopoetic stem cell transplantation
Although families A, B and C are not known to be related, they are believed to have a common ancestor.
1. Reported in Roscioli et al (2006); individuals AII.1, BII.1, BII.2, and CII.1 were included in the initial homozygosity mapping analysis.
2. Secondary to cerebral white matter abnormality (presumed cerebral toxoplasmosis)
3. IgA and IgM serum concentrations increased to lower limit of normal while on IVIG.
No significant difference in the clinical manifestations of VODI is observed between individuals with SP110 exon 2 and exon 5 mutations.
The one child with an exon 4 duplication (Patient F, Table 3) presented at age 11 months (later than average) with disseminated CMV infection, which has not been noted in other children with VODI. In addition, the numbers of memory T and B cells were normal and intracellular cytokine production was normal, findings not observed in other children with VODI.
Pathophysiology. It is currently unknown whether the hVOD is a direct manifestation of SP110 sequence variants, related to altered apoptosis in the hepatic sinusoid, or secondary to infection.
Penetrance for the combined B and T cell immunodeficiency has been 100% in individuals confirmed to have VODI caused by mutations in SP110. Likewise, hVOD has been described in all probands or their affected siblings.
Approximately 10% of children with VODI, ascertained at a young age because of an affected sib and treated early in the disease course with IVIG, may manifest immunodeficiency only at presentation.
VODI was described originally in Australians of Lebanese origin by Mellis & Bale (1976). Subsequently, the majority of children reported with VODI have been of Lebanese origin. The prevalence of VODI in the Lebanese population of Sydney, Australia, has been calculated to be one in 2,500 [Roscioli et al 2006].
The prevalence of VODI in children of non-Lebanese origin is unknown; however, the following reports suggest that the VODI phenotype is observed in other populations.
Additional reports of VODI:
A simplex case of VOD (i.e., a single occurrence in a family) with humoral and cellular immunodeficiency in the Spanish literature [Manzanares, Lopez-Manzanares et al 1992]
An Italian child with VODI [Ruga et al 2006]
A Hispanic child with hVOD and immunodeficiency from the United States on whom molecular genetic testing is in progress [Peck Ong, unpublished data]
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Although sinusoidal obstruction syndrome in association with severe combined immunodeficiency (SCID) was described in one case reported by Washington et al (1993), and in one post-mortem HIV cohort reported by Buckley & Hutchins (1995), the lack of a recognized and replicated association of immunodeficiency with hepatic veno-occlusive disease (hVOD) in other classes of immunodeficiency suggests that hVOD may be a primary feature of VODI rather than secondary to an immunodeficiency per se. No other associations of hVOD with immunodeficiency have been reported.
The primary differential diagnosis for hVOD alone would be environmental alkaloid or sinusoidal cell toxicity. However, hVOD has also been reported in association with alcoholic cirrhosis [Kishi et al 1999], ataxia-telangiectasia [Srisiriojanakorn et al 1999], osteopetrosis [Corbacioglu et al 2006], and hypereosinophilic syndrome [Kojima et al 1995].
Previous case-control studies using single-nucleotide polymorphisms (SNPs) have also reported associations between hVOD and SNPs in the carbamyl phosphate synthetase 1 (CPS1) (see Urea Cycle Disorders Overview), factor V Leiden (FVL), HFE (see HFE-Associated Hereditary Hemochromatosis), and glutathione S-transferase genes (GSTM1 and GSTT1). Relative risks of 8.6 for the homozygous HFE C282Y allele and 4.12 for the GSTM1 null allele have been reported [Srivastava et al 2004, Kallianpur 2005, Kallianpur et al 2005]. No independent replication of these findings has been performed.
There has been no report of SP110 mutations in individuals described to have hVOD alone.
To establish the extent of disease in an individual diagnosed with hepatic veno-occlusive disease with immunodeficiency (VODI):
Assessment of immune function including serum immunoglobulin levels, T and B cell numbers and percentages, and T cell proliferative response to mitogen
More extensive immune testing for number of memory B and T cells and intracellular cytokine (IL2, IL4, IL6, and IFNγ) responses to stimulation, if available
Complete blood count (CBC)
Assessment of hepatic function (including serum concentrations of aminotransferases, bilirubin, and albumin) and assessment for sequelae of portal hypertension (including anemia and thrombocytopenia)
A clotting profile and a hepatic Doppler ultrasound examination should be undertaken prior to consideration of hepatic biopsy for a histologic diagnosis of hepatic veno-occlusive disease (hVOD). Evidence of impaired clotting and/or portal hypertension are contraindications to hepatic biopsy.
Treatment of hypogammaglobulinemia via intravenous immunoglobulin should commence at the diagnosis of hepatic veno-occlusive disease with immunodeficiency (VODI) or in presymptomatic siblings confirmed to have homozygous SP110 mutations. An appropriate dose is 0.4g/kg every four to six weeks for a child and 0.3 g/kg every four to six weeks for an adult.
Pneumocystis jerovici prophylaxis with Cotrimoxazole® pediatric suspension (5 mL = trimethoprim 40 mg and sulfamethoxazole 200 mg) should be ongoing in children with VODI who tolerate this medication. This may be administered as a single daily dose or as a single dose three days per week. The recommended dose is 5 mg trimethoprim per kg (0.625 mL/kg) or 150 mg/M2 (3.75 mL/M2).
Infections with specific agents should be treated with appropriate supportive care and antibacterials or antivirals.
HSCT and hepatic transplantation may be considered, but appear to have a high rate of complications in the VODI cohort studied to date (see Other).
Initiation of regular intravenous immunoglobulin at the time of diagnosis to prevent infection related to severe hypogammaglobulinemia and Cotrimoxazole® prophylaxis to prevent Pneumocystis jerovici infection is appropriate (see Treatment of Manifestations).
Some evidence suggests that treatment of immunodeficiency early in VODI may reduce the risk of development or recurrence of hVOD.
Regular surveillance of hepatic function, platelet count, and hemoglobin level in children with VODI as hepatic failure and portal hypertension may occur
Measurement of immunoglobulin concentrations prior to IVIG infusions
Broncho-alveolar lavage to diagnose Pneumocystis jerovici infection; viral cultures or lung function studies as needed
Agents known to predispose to hVOD such as cyclophosphamide and senecio alkaloids/bush teas should be avoided.
The majority of children with VODI present before age six months; however, as one child presented at age 11 months, molecular genetic testing should be considered in sibs of a proband who are younger than than age 12 months.
Penetrance is complete (i.e., 100%) in the individuals with VODI described to date; thus, molecular genetic testing of healthy at-risk sibs of a proband who are older than age 12 months is not recommended.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapeutic agents for VODI that may be investigated in the future include those that suppress stop codons (readthrough agents), such as gentamicin and PTC124 [Aurino & Nigro 2006].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Hepatic VOD has been reported in the Australian cohort with VODI following HSCT; therefore, individuals with VODI are likely to have at least the population risk of hVOD after HSCT.
Other transplant modalities may also have an increased risk of other complications. Another child with VODI developed hemophagocytic syndrome after hepatic transplantation. The safety of these two transplant modalities in children with VODI compared to HSCT in other settings is not yet known.
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.
Hepatic veno-occlusive disease with immunodeficiency (VODI) is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes and therefore carry 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.
Penetrance is complete; asymptomatic homozygous individuals have not been identified.
Offspring of a proband. The offspring of an individual with hepatic veno-occlusive disease with immunodeficiency are obligate heterozygotes (carriers) for a disease-causing mutation in the SP110 gene.
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 available on a clinical basis once the mutations have been identified in the proband.
See Testing of Relatives at Risk for information on testing at-risk relatives who are younger than age 12 months 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.
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 where SP110 gene mutations have not been identified. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 11-12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified 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.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| SP110 | 2q37.1 | Sp110 nuclear body protein |
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.
| 235550 | HEPATIC VENOOCCLUSIVE DISEASE WITH IMMUNODEFICIENCY; VODI |
| 604457 | NUCLEAR BODY PROTEIN SP110; SP110 |
| Gene Symbol | Entrez Gene |
|---|---|
| SP110 | 3431 (MIM No. 604457) |
For a description of the genomic databases listed, click here.
Normal allelic variants: SP110 is expressed primarily in leukocytes and spleen; it is induced by interferon gamma and all-trans retinoic acid (ATRA).
The Sp110 nuclear body protein has three described major isoforms: Sp110 isoform A, NM_004509 (average mass 78.438 kd; transcript does not include exon 17); isoform B, NM_004510 (average mass 61.940 kd; transcript includes an alternate exon 15 and terminates within exon 15); isoform C, NM_080424 (average mass 81.211 kd; full-length transcript including exon 17 and terminating at exon 19). The Sp110b protein isoform has been described as showing activity as a potent transcriptional co-repressor of retinoic acid receptor alpha (RARα) perhaps via competitive exclusion of activators at receptor [Watashi et al 2003].
Pathologic allelic variants:
| Mutation | Exon | Reference | Phenotype |
|---|---|---|---|
| c.40delC (p.Q14SfsX25) | 2 | Roscioli et al 2006 | VODI |
| c.319_325dupGGTGCTT (p.S109WfsX5) | 4 | Ruga et al 2006 | VODI |
| c.642delC (p.P214PfsX14) | 5 | Roscioli et al 2006 | VODI |
Normal gene product: The Sp110 nuclear body protein is a member of the Sp100/Sp140 promyelocytic leukemia nuclear body (PML NB) protein family. The protein has an Sp100 domain (AA 6-159), which is involved in dimerization with other Sp100 family proteins, a nuclear localization signal (AA 288-306) and a nuclear hormone interaction domain (LXXLL type), which may act as an ATRA response element. Other domains that are common features of modular proteins involved in chromatin-mediated gene transcription include a SAND domain (AA 452-532), a plant homeobox domain (AA 537-577), and a bromodomain (AA 606-674) [Bloch et al 1996, Bloch et al 2000].
The Sp110 nuclear body protein is associated with the PML NB, a nuclear macromolecular complex, which is deployed to areas of active host or viral DNA replication, transcription, and repair and has been reported to be involved in apoptosis, cell cycle control, and the immune response.
Abnormal gene product: EBV-transformed B cells from an individual with VODI and a homozygous inactivating SP110 mutation have shown an absence of nuclear Sp100-specific immunolabeling in a setting of normal numbers of PML nuclear bodies. This finding is consistent with Sp110 protein having an important role in the immune response without being essential for PML nuclear body formation [Roscioli et al 2006].
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.
Immune Deficiency Foundation
40 W Chesapeake Ave Suite 308
Towson MD 21204
Phone: 800-296-4433; 410-321-6647
Fax: 410-321-9165
Email: idf@primaryimmune.org
www.primaryimmune.org
International Patient Organisation for Patients with Primary Immunodeficiencies
Firside Main Road
Downderry
Cornwall PL11 3LE
United Kingdom
Email: david@pia.org.uk
http://ipopi.org/
Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
747 Third Avenue 34A
New York NY 10017
Phone: 800-533-3844; 212-819-0200
Fax: 212-764-4180
Email: info@jmfworld.org
www.info4pi.org
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.
21 February 2007 (me) Review posted to live Web site
29 November 2006 (mb) Original submission
