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Updated: Jun 10, 2026
06:41
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Bi-allelic loss-of-function variants in TMEM63B cause syndromic surfactant dysfunction disorder.
Sock Hoai Chan1, Audra N Iness2, Jill A Rosenfeld2
1DNA Diagnostic and Research Laboratory, Department of Genomic Medicine, KK Women's and Children's Hospital, Singapore 229899, Singapore; Paediatric Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore.
American Journal of Human Genetics
|June 8, 2026
Summary
Bi-allelic loss-of-function variants in the Transmembrane protein 63B gene (TMEM63B) cause a new autosomal-recessive lung disorder. This surfactant dysfunction disorder presents with early-onset respiratory distress and developmental delay in children.
Area of Science:
- Genetics and Genomics
- Pulmonology
- Cell Biology
Background:
- Transmembrane protein 63B (TMEM63B) encodes a mechanosensitive ion channel crucial for surfactant secretion in lung alveolar type II cells.
- While gain-of-function variants are linked to neurological disorders, the impact of loss-of-function variants was unknown.
- This study investigates the role of bi-allelic TMEM63B loss-of-function in human disease.
Purpose of the Study:
- To identify the genetic cause of a novel childhood interstitial lung disease.
- To characterize the clinical, histopathological, and genetic features of TMEM63B-related lung disorder.
- To establish the link between TMEM63B variants and impaired surfactant homeostasis.
Main Methods:
- Whole-exome sequencing and segregation analysis to identify causative variants.
- Clinical evaluation, chest imaging, and lung histopathology of affected individuals.
- Functional studies to confirm the loss-of-function mechanism of identified variants.
- Comparison with Tmem63b-knockout mouse models.
Main Results:
- Five individuals from four families presented with early-onset respiratory distress, hypoxemia, and diffuse lung abnormalities due to bi-allelic TMEM63B loss-of-function variants.
- Lung pathology revealed alveolar simplification, type II pneumocyte hyperplasia, and interstitial fibrosis, indicating surfactant dysfunction.
- Affected individuals also exhibited developmental delay, primarily affecting speech and language.
- The pulmonary phenotype mirrored that of Tmem63b-knockout mice.
Conclusions:
- Bi-allelic loss-of-function variants in TMEM63B define an autosomal-recessive syndromic surfactant dysfunction disorder.
- This expands the known phenotypic spectrum of TMEM63B-associated diseases beyond the central nervous system.
- TMEM63B is essential for maintaining pulmonary surfactant homeostasis and normal lung development.
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