# Family with Sequence Similarity 20, Member C (FAM20C) and Brain Calcification

> **NIH NIH R03** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2021 · $151,500

## Abstract

PROJECT SUMMARY
Brain calcification is a common neuroimaging finding in individuals with a variety of hereditary or nonhereditary
syndromes or many other acquired medical conditions. Raine syndrome, a rare autosomal recessive disease, is
caused by mutations in the Family with sequence similarity 20, member C (FAM20C) gene. It is characterized
by skeletal and dental defects along with brain calcification. Mouse genetic studies have shown that Sox2-
cre;Fam20cfl/fl mice, in which Fam20c was deleted in nearly all the body tissues and cells, developed
hypophosphatemic rickets/osteomalacia as well as dental abnormalities. FAM20C encodes a Golgi-localized
protein kinase that phosphorylates secretory proteins, including osteopontin (OPN) and matrix extracellular
phosphoglycoprotein (MEPE) – two members of the Small Integrin-Binding LIgand N-linked Glycoprotein
(SIBLING) family. Both OPN and MEPE contain an acidic serine- and aspartate-rich motif (ASARM). Previous
studies have demonstrated that OPN and the ASARM peptides derived from OPN and MEPE proteins inhibit
mineralization, and such inhibitory effects depend on the extent of their phosphorylation. While significant
progresses have been made in understanding the functions of FAM20C in osteogenesis and odontogenesis, the
pathogenic mechanisms underlying the brain calcification in Raine syndrome patients remain largely unknown.
More recently, the principal investigator (PI) have found that 1) Fam20c is widely expressed in the mouse brain;
2) Sox2-cre;Fam20cfl/fl mice develop apparent brain calcification by the age of postnatal 3 months; and 3)
osteopontin (Opn), a member of SIBLING family, is expressed in the mouse brain neurons. These new findings
together with the previous findings on FAM20C and the SIBLING proteins lead to the novel hypothesis that the
loss of FAM20C function in the brain cells causes the failure of phosphorylation of OPN and MEPE
proteins, resulting in brain calcification. Two specific aims are proposed to test this hypothesis: Aim 1 is to
determine if the calcification is associated with the loss of FAM20C function in the brain in Sox2-cre;Fam20cfl/fl
mice. To complete this aim, the PI will map the locations of the brain calcifications in Sox2-cre;Fam20cfl/fl mice
with age and correlate the calcifications with the loss of FAM20C function in each brain structure. Aim 2 is to
determine if OPN and MEPE are phosphorylated in the brain tissues of the control mice, and if the
phosphorylation of these two proteins is lost in Sox2-cre;Fam20cfl/fl mice. To fulfill this aim, the PI will isolate
OPN and MEPE proteins from the brain tissues of Fam20cfl/fl (control) and Sox2-cre;Fam20cfl/fl mice, and then
determine and compare the overall phosphorylation levels and phosphorylation sites of these two proteins
between Fam20cfl/fl and Sox2-cre;Fam20cfl/fl mice. Successful completion of the proposed studies will provide
new insights into our understanding of how ectopic calcification is prevented ...

## Key facts

- **NIH application ID:** 10217493
- **Project number:** 1R03NS116744-01A1
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Hua Zhang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $151,500
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217493

## Citation

> US National Institutes of Health, RePORTER application 10217493, Family with Sequence Similarity 20, Member C (FAM20C) and Brain Calcification (1R03NS116744-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10217493. Licensed CC0.

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