# Pathogenic Mechanisms in Christianson Syndrome and NHE6-Related Disorders > **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $795,923 ## Abstract PROJECT SUMMARY Endolysosomal dysfunction is a convergent mechanism in many brain disorders. We are studying genetic con- ditions caused by mutations in the endosomal Na+/H+ Exchanger 6 (NHE6). Through our work with affected families in the International Christianson Syndrome and NHE6 Gene Network Study, we have found three phe- notypes associated with NHE6 mutations: 1) Christianson Syndrome (CS), a profound intellectual disability af- fecting males with loss-of-function mutations; 2) the Female-specific NHE6 Mutation Carrier Syndrome (FCS); and 3) Non-Syndromic ID/Autism (NS-ID/ASD) which occurs in males who carry putative hypomorphic muta- tions in NHE6. The objective of this R01 renewal proposal is to define pathogenic mechanisms that cause NHE6-related disease, as well as to develop mechanistic linkages to other related developmental and degen- erative disorders. We find a high degree of relevance to Lysosome Disorders, as well as, Alzheimer’s Disease (AD) and AD-Related Dementias (ADRD). Our central hypothesis is that loss of NHE6 leads to abnormal endo- some-lysosome fusion, thereby causing: 1) cell-autonomous defects, such as aberrant retrograde axonal transport and lysosomal deficiency; and 2) cell non-autonomous pathology, such as toxic exosome release, and activation of disease-associated glial. Our research team is in an excellent position to study NHE6-related disease bench-to-bedside. We have unique resources, including: NHE6 mutant mice and human stem cells; as well as an NHE6-null rat that shows endogenous tauopathy. We also have a long-standing relationship with the family-led Christianson Syndrome Association, as we lead the natural history studies. There are four Aims: Aim 1 focuses on defining the molecular mechanism whereby loss of NHE6 leads to an endosome-lysosome fusion defect. In Aim 2, we define molecular mechanisms governing the emergence of disease-associated astrocytes and microglia in NHE6-mutant brains. The impact of this Aim, in part, involves the strong overlap of disease- associated glial states with AD/ADRD. In Aim 3, we will define the mechanism whereby putative hypomorphic NHE6 mutations in patients with NS-ID/ASD cause developmental delays and behavioral regressions. In this Aim, we will dissect biological mechanisms in developmental regression, which are common but have re- mained largely undefined. In Aim 4, we will focus on FCS, and define potential cell non-autonomous disease mechanisms in female NHE6 mutation carriers, including assessment of tau toxicity. In this Aim, through study of patient-derived iPSCs and the female carrier rat, we will contribute to knowledge of the understudied female carrier syndrome, and also to elucidating disease mechanisms related to X-chromosome inactivation in female brain. Overall, this research will define mechanisms in new genetic diseases in males and females, and will establish linkages with more common disorders, including AD/ADRD, potentially identifying new therape... ## Key facts - **NIH application ID:** 10990047 - **Project number:** 2R01NS113141-06 - **Recipient organization:** BROWN UNIVERSITY - **Principal Investigator:** Eric M Morrow - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $795,923 - **Award type:** 2 - **Project period:** 2019-09-15 → 2029-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10990047 ## Citation > US National Institutes of Health, RePORTER application 10990047, Pathogenic Mechanisms in Christianson Syndrome and NHE6-Related Disorders (2R01NS113141-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10990047. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*