# Sex Chromosome Aneuploidies in Autoimmune Disease

> **NIH VA I01** · OKLAHOMA CITY VA MEDICAL CENTER · 2021 · —

## Abstract

Abstract
Systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) are chronic, inflammatory, autoimmune
diseases. Some features of these illnesses are similar. These include aspects of clinical manifestations,
serology and epidemiology. Most critical for this proposal is that there is a strong female bias found for both
diseases such that at least 90% of patients are women. The mechanism for this sex bias was unexplained
until the work of the PI, which began more than a decade ago and was funded in part by this VA Merit Review
for which a renewal is sought. The PI and his colleagues found that men with 47,XXY (Klinefelter’s syndrome)
are at the same risk of SLE or SS as women. In addition, 47,XXX women are at increased risk of either
disease compared to women carrying a 46,XX chromosomal complement. This X chromosome dose effect
was found for SLE and SS but not rheumatoid arthritis, primary biliary cirrhosis or sarcoidosis. Thus, our data
indicate multiple molecular pathways to female-biased disease. In cells with more than one X chromosome, all
but one undergoes X inactivation. However, X inactivation in humans is not an all-or-none process such that
up to 15% of genes on the X chromosome escape inactivation. That is, these genes are transcribed and
translated from both X chromosomes (biallelically) in normal (46,XX) women. We have identified two X
chromosomes genes that escape X inactivation in immune cells and are both involved in toll like receptor
(TLR) 7 signaling to produce interferon, and have a lupus risk allele identified in genome-wide association
studies. Namely, these genes are TLR7 itself and CXorf21. The protein product of CXorf21 physically
interacts with the protein product of another lupus risk gene – SLC15a4. In studies performed in the previous
cycle of this award, and published in 2019, we find that CXorf21 and SLC15a4 regulate endolysosomal pH and
are critical for TLR7 signaling. Knockdown of CXorf21 by CRISPR-Cas9 raises endolysosomal pH (less
conducive to TLR7 signaling), and impairs TLR7 signaling with marked reduction of interferon as well as other
cytokine production (see Progress Report and Preliminary Data). Of course, interferon production through
TLR7 signaling is known to be a critical aspect of lupus pathogenesis in both human and murine lupus. Thus,
these data constitute a strong premise for the work proposed herein. Much of the genetics of SLE has not
been identified by GWAS, and much of this missing genetics may be related to presently unidentified genetic
synergism. In the first aim, we will determine the degree of genetic synergism found in the interaction of the
lupus-associated alleles of these genes involved in the TLR7 pathway. This aim will use our cohort of >300
men with SLE, the largest cohort ever assembled by more than 3-fold. In the second aim, we will define the
physiological roles of the protein products of these genes in the TLR signaling pathway with particular attention
to the associated ...

## Key facts

- **NIH application ID:** 10124545
- **Project number:** 2I01BX001451-09
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** Robert Hal Scofield
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2012-04-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124545

## Citation

> US National Institutes of Health, RePORTER application 10124545, Sex Chromosome Aneuploidies in Autoimmune Disease (2I01BX001451-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124545. Licensed CC0.

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