# BIOCHEMICAL GENETICS OF CHILDHOOD IMMUNODEFICIENCY

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 1994 · $257,565

## Abstract

Inherited deficiency of adenosine deaminase (ADA) causes a fatal childhood
illness, severe combined immunodeficiency disease.  Underlying the
immunodeficiency are profound disturbances of adenosine and deoxyadenosine
metabolism.  Abnormal metabolites that accumulate in ADA pattern of
expression.  In humans there is very high level expression in thymocytes,
much lower in mature T-cells, and generally lower yet in most other
tissues.  One exception, for example, is the mucosa of stomach and duodenum
that also exhibits a level of expression comparable to thymus.  The rate at
which the ADA gene is transcribed varies in a cell-type specific fashion,
and closely parallels ADA activity levels.  The first intron (15 kb)
contains a complex array of cis-active elements that determine, at least in
part, the rate at which the ADA gene is transcribed.  Only one sub-region
of the first intron appears to contain T-cell specific enhancer activity.
Since data from bone-marrow transplant-corrected ADA deficient patients
indicate that lymphoid-reconstitution alone corrects the immunodeficiency,
it is important to determine the molecular mechanisms that underly high
level ADA expression in thymocytes.  Our basic hypothesis is that one or
more specific DNA sequences (core enhancer elements) in the first intron of
the human ADA gene interact with cell-type specific DNA binding proteins to
regulate ADA expression during differentiation of thymocytes and T-
lymphocytes.  Testing of this hypothesis will be the major objective of the
proposed work and will employ the following specific aims:  (1)
characterize the cis-regulatory elements(s) within the first intron of he
human ADA gene that act as specific enhancers of transcription in
thymocytes and T-lymphocytes; (2) purify and characterize thymic protein(s)
that bind to the core enhancer element(s) and assess their involvement in
regulating the developmental expression of the human gene during T-lymphoid
differentiation; and (3) clone and functionally characterize the cDNA(s)
and gene(s) that encode the human thymic enhancer binding protein(s).
Assignment of functions to putative core enhancer elements and specific
enhancer binding protein(s) will require extensive use of transgenic mice
and transfection/transient expression assay in cell culture.  The expected
outcome is an understanding of the molecular mechanism of regulation of ADA
expression in human T-lymphocytes and their precursors.

## Key facts

- **NIH application ID:** 2197896
- **Project number:** 5R01HD019919-11
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **SAM.gov UEI:** JZD1HLM2ZU83
- **Principal Investigator:** JOHN J HUTTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $257,565
- **Award type:** 5
- **Project period:** 1984-08-01 → 1995-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2197896

## Citation

> US National Institutes of Health, RePORTER application 2197896, BIOCHEMICAL GENETICS OF CHILDHOOD IMMUNODEFICIENCY (5R01HD019919-11). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2197896. Licensed CC0.

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