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A Novel Mutation of the Spectrin Gene

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ClinicalTrials.gov Identifier: NCT00723567
Recruitment Status : Completed
First Posted : July 28, 2008
Last Update Posted : February 19, 2009
Sponsor:
Collaborator:
Information provided by:

Study Description
Brief 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.

Condition or disease
Hereditary Elliptocytosis (HE) Hereditary Pyropoikilocytosis (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:

  1. Quantitation of erythrocyte (RBC) membrane proteins
  2. DNA extraction from the WBC and screening for spectrin mutation with restriction enzymes (if needed we will sequence spectrin gene)
  3. Quantitative Real Time PCR testing will be done on RNA to assess the spectrin gene expression
  4. 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

Study Type : Observational
Actual Enrollment : 12 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Case Report: A Novel Mutation of the Spectrin Gene in a Family of Northern European Descent Is Associated With Three Different Phenotypes
Study Start Date : February 2008
Primary Completion Date : December 2008
Study Completion Date : December 2008


Groups and Cohorts

Group/Cohort
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.


Outcome Measures

Primary Outcome Measures :
  1. 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 ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   7 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
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.
Criteria

Inclusion Criteria:

  • > 7 years of age
  • Consenting family members

Exclusion Criteria:

  • Anyone not meeting the criteria above
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00723567


Locations
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
University of Utah
University of Witwatersrand, South Africa
Investigators
Principal Investigator: Josef T Prchal, MD University of Utah
More Information

Publications:
Responsible Party: Josef T. Prchal, MD, University of Utah
ClinicalTrials.gov Identifier: NCT00723567     History of Changes
Other Study ID Numbers: 27669
First Posted: July 28, 2008    Key Record Dates
Last Update Posted: February 19, 2009
Last Verified: February 2009

Keywords provided by University of Utah:
Spectrin Gene
Hereditary Elliptocytosis (HE)
Hereditary Pyropoikilocytosis (HPP)
Genetics

Additional relevant MeSH terms:
Elliptocytosis, Hereditary
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Genetic Diseases, Inborn