# Molecular Analysis of primary cilia proteins in human development and disease

> **NIH NIH R35** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $29,010

## Abstract

The goal of the research in my laboratory is to study the genetic basis of human craniofacial and
CNS malformations. Our efforts in both human and mouse genetics over the past several years
have continually directed us towards the primary cilium as a critical hub in signaling for human
health and disease. Ciliopathies are diseases associated with both severe congenital
malformations as well as nonlethal craniofacial dysmorphology, intellectual disability and obesity
(among other conditions). It is clear from the literature that modifying loci are crucial
components in understanding much of human disease, but is especially true of the ciliopathies.
The focus of this proposal is largely on the primary cilia gene tetratricopeptide repeat domain
21B (Ttc21b). Ttc21b homozygous mouse mutants have several striking features on their own but
our preliminary data and the work of others clearly show that TTC21B is a hub in a human
ciliopathy network. We have taken four of these candidate interactions from human genetics and
recreated them in mouse. All four genes interact with Ttc21b but the cellular and mechanisms of
the resulting phenotypes are not yet elucidated. We have also identified multiple novel
interacting loci with a combination of ENU mutagenesis and a QTL analysis of the genetic
background effects on the severity of the microcephaly phenotype. Thus, we have significant
experience in the field and have identified four crucial gaps in knowledge we will address with
the support of this MIRA award: 1) How does Ttc21b have such tissue specific effects on organ
physiology and developmental signaling, 2) What are the genetic interactors and modifiers of
Ttc21b which alter these ciliopathy phenotypes, 3) what is the cellular function of Ttc21b inside
the primary cilium, 4) what is the role of Ttc21b outside the cilium. We will use a combination of
genetics, molecular embryology, cell biology and biochemistry to address these topics. Many of
the ciliary genes are identified to have roles within the primary cilium, but any function outside
the cilium has not been elucidated. Identification of such roles would have very a significant
effect on the field. Our favorite hypothesis based on preliminary data is that Ttc21b has
significant roles in neuronal trafficking. It is clear that a better understanding of human disease
will require knowledge of modifying loci and the underlying mechanism(s). Ttc21b is ripe for
exploration as a crucial component in a ciliopathy genetic network. A combination of mouse
embryology and cell biology inspired by human genomics is an ideal entry point. Our work is likely
to not only contribute to knowledge about ciliopathies but point the way forward as a general
experimental paradigm for a number of different pathophysiological contexts.

## Key facts

- **NIH application ID:** 10135118
- **Project number:** 5R35GM131875-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Rolf W Stottmann
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $29,010
- **Award type:** 5
- **Project period:** 2019-05-15 → 2021-06-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135118

## Citation

> US National Institutes of Health, RePORTER application 10135118, Molecular Analysis of primary cilia proteins in human development and disease (5R35GM131875-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10135118. Licensed CC0.

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