Hereditary Elliptocytosis (HE)NCT00723567
A Novel Mutation of the Spectrin Gene
An observational study of Hereditary Elliptocytosis (HE) and Hereditary Pyropoikilocytosis (HPP), run by University of Utah at 1 site in United States.
Trial summary
The purpose of this study is to find a gene or its mutation (an altered gene) that puts individuals at risk for developing HE or HPP. Read more about this study
- Who is it for?
- Ages 7 years and olderHealthy volunteers can take part
- Conditions the study is for
- Hereditary Elliptocytosis (HE), Hereditary Pyropoikilocytosis (HPP)
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2008to Dec 2008
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 7 years and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Members from a family of northern European descent in which members had different erythrocyte morphology ranging from atypical HPP to HE to normal and a novel Sp mutation.
Who may be able to join
- > 7 years of age
- Consenting family members
Who cannot join
- Anyone not meeting the criteria above
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Case Report: A Novel Mutation of the Spectrin Gene in a Family of Northern European Descent Is Associated With Three Different Phenotypes
The purpose of this study is to find a gene or its mutation (an altered gene) that puts individuals at risk for developing HE or HPP.
Read the detailed description
Mutations of spectrin (Sp) involving the Sp heterodimer self-association site (the I domain of Sp) represent the most common group of membrane skeletal defects in hereditary elliptocytosis (HE) and a closely related disorder, hereditary pyropoikilocytosis (HPP). HPP is characterized by extreme anisocytic microcytosis, a severe spectrin dimer self-association defect and spectrin deficiency. The conventional explanation for the different phenotypes is that HPP subjects are compound heterozygotes for an sp defect that interferes with sp tetramer assembly and a second defect which results in decreased synthesis of functional sp. In contrast, HE subjects have normal spectrin content and a less severe sp self-association defect. The clinical expression of HE/HPP is influenced by the inheritance of modifying factors such as the Sp hypomorphic mutation, LELY. LELY is a low expression allele of the Sp gene characterized by a C>G mutation in codon 1857 of exon 40 and a C>T -12 mutation in intron 45 that is responsible for partial skipping of exon 46, which is essential for the functional assembly of /b sp dimers.
CASE REPORT:
Here we describe four members from a family of northern European descent in which members had different erythrocyte morphology ranging from atypical HPP to HE to normal and a novel Sp mutation. Quantitation of RBC membrane proteins of the propositus with atypical non-microcytic HPP revealed 48% spectrin dimers (control 10%) due to a marked increase in the 74kD I Sp peptide. There was only a slight decrease in the spectrin/band 3 ratio, which correlated with the normocytic morphology. There was also an abnormal Sp peptide at 41kD suggesting presence of LELY. Sequencing of his Sp gene revealed heterozygosity for a novel mutation in exon 2, codon 34: CGG->CCG (Arg>Pro) and heterozygosity for LELY. These mutations were also present in his brother and daughter who have HE, while another son, who had Arg34Pro, but not LELY has repeatedly confirmed normal morphology.
We plan to screen 11 other family members who are suspected to have HPP or HE. Blood samples will be obtained and the following will be performed:
- Quantitation of erythrocyte (RBC) membrane proteins
- DNA extraction from the WBC and screening for spectrin mutation with restriction enzymes (if needed we will sequence spectrin gene)
- Quantitative Real Time PCR testing will be done on RNA to assess the spectrin gene expression
- History, Clinical examination, CBC, chemistry and peripheral blood smear
Quantitation of RBC membrane proteins will be done by looking for the abnormal increase in the amount of spectrin dimers in patients with HPP (control 10%). We will also look at the DNA for any known or yet unreported mutations in the spectrin gene and we will correlate the expression of spectrin gene wrt level of spectrin protein in the RNA.
No statistical analysis will be done. This is an observation study designed to correlate clinical features with the above mentioned tests results.
- Keywords
- Spectrin Gene, Hereditary Elliptocytosis (HE), Hereditary Pyropoikilocytosis (HPP), Genetics
- Medical subject headings
- Elliptocytosis, Hereditary, Pyropoikilocytosis, Hereditary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Affected Group | Family members of northern European descent in which members have different erythrocyte morphology ranging from atypical HPP to HE to normal and a novel Sp mutation. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Identify a gene or its mutation (an altered gene) that puts individuals at risk for developing HE or HPP
Measured: After sample is obtained
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jul 2008 (estimated)
- Study startFeb 2008
- Primary completionDec 2008
- Study completionDec 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Hereditary Elliptocytosis (HE)Studies of the same condition, open and under way.
- More trials run by University of UtahThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Utah
- Sponsor type
- University, hospital or other
- Collaborators
- University of Witwatersrand, South Africa
- Investigators
- Josef T Prchal, MD, Principal investigator, University of Utah
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00723567
- Sponsor's protocol ID
- 27669
- Status last verified
- Feb 2009
- First submitted
- 24 Jul 2008
- Last updated
- 19 Feb 2009
- Results posted
- No
- Data monitoring committee
- No
Publications
Ivanov IT, Tolekova A, Chakaarova P. Erythrocyte membrane defects in hemolytic anemias found through derivative thermal analysis of electric impedance. J Biochem Biophys Methods. 2007 Jun 10;70(4):641-8. doi: 10.1016/j.jbbm.2007.02.004. Epub 2007 Mar 1.
PubMed 17395266Ramos MC, Schafernak KT, Peterson LC. Hereditary pyropoikilocytosis: a rare but potentially severe form of congenital hemolytic anemia. J Pediatr Hematol Oncol. 2007 Feb;29(2):128-9. doi: 10.1097/MPH.0b013e3180320b6f.
PubMed 17279012King MJ, Telfer P, MacKinnon H, Langabeer L, McMahon C, Darbyshire P, Dhermy D. Using the eosin-5-maleimide binding test in the differential diagnosis of hereditary spherocytosis and hereditary pyropoikilocytosis. Cytometry B Clin Cytom. 2008 Jul;74(4):244-50. doi: 10.1002/cyto.b.20413.
PubMed 18454487An X, Mohandas N. Disorders of red cell membrane. Br J Haematol. 2008 May;141(3):367-75. doi: 10.1111/j.1365-2141.2008.07091.x. Epub 2008 Mar 12.
PubMed 18341630Gaetani M, Mootien S, Harper S, Gallagher PG, Speicher DW. Structural and functional effects of hereditary hemolytic anemia-associated point mutations in the alpha spectrin tetramer site. Blood. 2008 Jun 15;111(12):5712-20. doi: 10.1182/blood-2007-11-122457. Epub 2008 Jan 24.
PubMed 18218854Salomao M, Zhang X, Yang Y, Lee S, Hartwig JH, Chasis JA, Mohandas N, An X. Protein 4.1R-dependent multiprotein complex: new insights into the structural organization of the red blood cell membrane. Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8026-31. doi: 10.1073/pnas.0803225105. Epub 2008 Jun 4.
PubMed 18524950
Study at a glance
From the registry record, last updated by the sponsor on 19 Feb 2009. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Case Report: A Novel Mutation of the Spectrin Gene in a Family of Northern European Descent Is Associated With Three Different Phenotypes
- ClinicalTrials.gov ID
- NCT00723567
- Acronym / sponsor ID
- 27669
- Keywords
- Spectrin Gene, Hereditary Elliptocytosis (HE), Hereditary Pyropoikilocytosis (HPP), Genetics
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- University of UtahUniversity, hospital or other
- Collaborators
- University of Witwatersrand, South Africa
- Study start
- Feb 2008
- Primary completion
- Dec 2008 (actual)
- Study completion
- Dec 2008 (actual)
- First posted
- 28 Jul 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to find a gene or its mutation (an altered gene) that puts individuals at risk for developing HE or HPP.
Detailed description
Mutations of spectrin (Sp) involving the Sp heterodimer self-association site (the I domain of Sp) represent the most common group of membrane skeletal defects in hereditary elliptocytosis (HE) and a closely related disorder, hereditary pyropoikilocytosis (HPP). HPP is characterized by extreme anisocytic microcytosis, a severe spectrin dimer self-association defect and spectrin deficiency. The conventional explanation for the different phenotypes is that HPP subjects are compound heterozygotes for an sp defect that interferes with sp tetramer assembly and a second defect which results in decreased synthesis of functional sp. In contrast, HE subjects have normal spectrin content and a less severe sp self-association defect. The clinical expression of HE/HPP is influenced by the inheritance of modifying factors such as the Sp hypomorphic mutation, LELY. LELY is a low expression allele of the Sp gene characterized by a C>G mutation in codon 1857 of exon 40 and a C>T -12 mutation in intron 45 that is responsible for partial skipping of exon 46, which is essential for the functional assembly of /b sp dimers.
CASE REPORT:
Here we describe four members from a family of northern European descent in which members had different erythrocyte morphology ranging from atypical HPP to HE to normal and a novel Sp mutation. Quantitation of RBC membrane proteins of the propositus with atypical non-microcytic HPP revealed 48% spectrin dimers (control 10%) due to a marked increase in the 74kD I Sp peptide. There was only a slight decrease in the spectrin/band 3 ratio, which correlated with the normocytic morphology. There was also an abnormal Sp peptide at 41kD suggesting presence of LELY. Sequencing of his Sp gene revealed heterozygosity for a novel mutation in exon 2, codon 34: CGG->CCG (Arg>Pro) and heterozygosity for LELY. These mutations were also present in his brother and daughter who have HE, while another son, who had Arg34Pro, but not LELY has repeatedly confirmed normal morphology.
We plan to screen 11 other family members who are suspected to have HPP or HE. Blood samples will be obtained and the following will be performed:
- Quantitation of erythrocyte (RBC) membrane proteins
- DNA extraction from the WBC and screening for spectrin mutation with restriction enzymes (if needed we will sequence spectrin gene)
- Quantitative Real Time PCR testing will be done on RNA to assess the spectrin gene expression
- History, Clinical examination, CBC, chemistry and peripheral blood smear
Quantitation of RBC membrane proteins will be done by looking for the abnormal increase in the amount of spectrin dimers in patients with HPP (control 10%). We will also look at the DNA for any known or yet unreported mutations in the spectrin gene and we will correlate the expression of spectrin gene wrt level of spectrin protein in the RNA.
No statistical analysis will be done. This is an observation study designed to correlate clinical features with the above mentioned tests results.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Affected Group | – | –Family members of northern European descent in which members have different erythrocyte morphology ranging from atypical HPP to HE to normal and a novel Sp mutation. |
Who may qualify
- Ages
- 7 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Members from a family of northern European descent in which members had different erythrocyte morphology ranging from atypical HPP to HE to normal and a novel Sp mutation.
Key inclusion criteria (2 listed)
- > 7 years of age
- Consenting family members
Key exclusion criteria (1 listed)
- Anyone not meeting the criteria above
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Identify a gene or its mutation (an altered gene) that puts individuals at risk for developing HE or HPP
Time frame: After sample is obtained
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Feb 2009.
- Background: PubMed 17395266Ivanov IT, Tolekova A, Chakaarova P. Erythrocyte membrane defects in hemolytic anemias found through derivative thermal analysis of electric impedance. J Biochem Biophys Methods. 2007 Jun 10;70(4):641-8. doi: 10.1016/j.jbbm.2007.02.004. Epub 2007 Mar 1.
- Background: PubMed 17279012Ramos MC, Schafernak KT, Peterson LC. Hereditary pyropoikilocytosis: a rare but potentially severe form of congenital hemolytic anemia. J Pediatr Hematol Oncol. 2007 Feb;29(2):128-9. doi: 10.1097/MPH.0b013e3180320b6f.
- Background: PubMed 18454487King MJ, Telfer P, MacKinnon H, Langabeer L, McMahon C, Darbyshire P, Dhermy D. Using the eosin-5-maleimide binding test in the differential diagnosis of hereditary spherocytosis and hereditary pyropoikilocytosis. Cytometry B Clin Cytom. 2008 Jul;74(4):244-50. doi: 10.1002/cyto.b.20413.
- Background: PubMed 18341630An X, Mohandas N. Disorders of red cell membrane. Br J Haematol. 2008 May;141(3):367-75. doi: 10.1111/j.1365-2141.2008.07091.x. Epub 2008 Mar 12.
- Background: PubMed 18218854Gaetani M, Mootien S, Harper S, Gallagher PG, Speicher DW. Structural and functional effects of hereditary hemolytic anemia-associated point mutations in the alpha spectrin tetramer site. Blood. 2008 Jun 15;111(12):5712-20. doi: 10.1182/blood-2007-11-122457. Epub 2008 Jan 24.
- Background: PubMed 18524950Salomao M, Zhang X, Yang Y, Lee S, Hartwig JH, Chasis JA, Mohandas N, An X. Protein 4.1R-dependent multiprotein complex: new insights into the structural organization of the red blood cell membrane. Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8026-31. doi: 10.1073/pnas.0803225105. Epub 2008 Jun 4.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Josef T Prchal, MD principal investigator
University of Utah
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Hereditary Elliptocytosis (HE) and Hereditary Pyropoikilocytosis (HPP), run by University of Utah at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Feb 2009. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Identify a gene or its mutation (an altered gene) that puts individuals at risk for developing HE or HPP (time frame: After sample is obtained). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00723567, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Feb 2009.