# Genetic Mechanisms of Amelogenesis Imperfecta

> **NIH NIH R56** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $402,467

## Abstract

Amelogenesis imperfecta (AI) is a diverse collection of about 90 inherited conditions all manifesting enamel
malformations, and each caused by defects in a different gene. Many AI cases are isolated (only exhibit enamel
defects). Others are syndromic. The syndromes can involve very serious health problems, including blindness,
kidney calcifications, immunodeficiency, skin fragility, epilepsy, etc. Primary teeth start to erupt at 6 months so
enamel defects are often an early sign of a larger disease, and the only apparent phenotype at the time of
diagnosis. As some systemic conditions can be mitigated by early medical intervention, an early and accurate
diagnosis can minimize the effects of the condition on the patient's health. Without an accurate genetic diagnosis,
early intervention to mitigate pending systemic deterioration cannot be employed. A barrier to making a genetic
diagnosis of AI conditions is incomplete knowledge of the genes and mutations that can cause isolated and
syndromic forms of AI. This barrier is addressed in SA1: to recruit and characterize AI families to determine their
genetic etiology, identify new causative genes and mutations, and facilitate genetic testing.
 Once an AI proband is identified, a pedigree is constructed, and mode of inheritance assessed. Medical and
dental histories are reviewed and dental records obtained. If a non-dental phenotype is ascertained, a medical
consultation is coordinated with the physician. Subject DNA is characterized by whole-exome sequence (WES)
analyses. WES analyses cover about 85% of all disease-causing mutations. Advances made in SA1 will increase
knowledge of the genes and mutations that cause AI, enhance clinical genetic counseling, and result in practical
advancements in gene-based testing, diagnosis, and intervention to improve patient prognoses.
 Until recently the greatest barrier to understanding the molecular mechanisms of dental enamel formation
was a lack of knowledge of the critical molecular participants. Genetics has identified many new critical
genes/proteins, so now the greatest barrier is understanding their functions. This barrier is addressed in SA2: to
generate and characterize mouse models with defects homologous to human mutations to validate genetic
discoveries, and define normal and disease mechanisms. Specific hypotheses are tested in wild-type and
genetically modified mice concerning the normal function and pathological consequences of a loss of function of
four genes critical for dental enamel formation: odontogenesis associated phosphoprotein (Odaph), acid
phosphatase 4 (Acp4), RELT tumor necrosis factor receptor (Relt), and integrin beta 6 (Itgb6). OdaphC41*/C41*
mice show a specific failure of post-secretory transition (PST) of ameloblasts into maturation, offering unique
opportunities to understand the molecular mechanisms of PST. ACP4 is distinguished as either a lysosomal or
secreted protein. The ligand that binds the RELT receptor is identified. The ...

## Key facts

- **NIH application ID:** 10453477
- **Project number:** 2R56DE015846-16
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** JAN Ching Chun HU
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,467
- **Award type:** 2
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453477

## Citation

> US National Institutes of Health, RePORTER application 10453477, Genetic Mechanisms of Amelogenesis Imperfecta (2R56DE015846-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10453477. Licensed CC0.

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