Start where you are
Patients & Families
What is CMD2D in plain language? What testing, treatment, and support exist today? A family-friendly guide and FAQ.
Researchers
The gene, the variant spectrum, the dual loss-/gain-of-function mechanism, open scientific questions, and the primary literature.
Clinicians
Recognizing neonatal DCM with biallelic RPL3L variants: presentation, differential diagnosis, and management landscape.
Why RPL3L matters
Every cell builds proteins with ribosomes — but the heart and skeletal muscle use a specialized ribosome in which the core protein RPL3 is swapped for its muscle-specific paralog, RPL3L. Since 2020, biallelic variants in RPL3L have been shown to cause a rare, autosomal recessive, neonatal-onset dilated cardiomyopathy (CMD2D) that progresses rapidly to heart failure and is fatal without transplantation. Only a handful of families are described worldwide — which is exactly why it needs a dedicated initiative: rare diseases with few patients are systematically under-recognized and under-studied.
Our mission
Connect
Build the global registry of CMD2D patients and families. With so few known cases, every family transforms the science.
Accelerate research
Drive functional studies of RPL3L variants, model development, and exploration of therapies that exploit the RPL3–RPL3L paralog system.
Educate
Give families plain-language answers and give clinicians the recognition tools to shorten the diagnostic odyssey.
Advocate
Ensure neonatal DCM workups include ribosomal-protein genes, and that rare-cardiomyopathy voices are heard by regulators and the rare-disease community.
The story so far
Gene & ribosome biology Disease (CMD2D)
- 1996 — RPL3L is discovered: Van Raay et al. clone the gene from a human heart cDNA library while mapping the polycystic kidney disease region on 16p13.3 — and find its expression restricted to heart and skeletal muscle, a surprise for a "housekeeping" ribosomal protein.
- 2016 — First evidence that RPL3L specializes the ribosome: forced expression in myoblasts impairs myotube growth and fusion, establishing ribosome specialization as a real phenomenon in skeletal muscle.
- 2018 — First disease hint: population sequencing links RPL3L coding variants to atrial fibrillation risk (Thorolfsdottir et al.).
- 2020 — The disease is defined: Ganapathi et al. report five children from three families with severe neonatal DCM caused by biallelic RPL3L missense variants — the first cytoplasmic ribosomal protein linked to non-syndromic cardiomyopathy. CMD2D enters OMIM (619371); a homozygous case (p.Arg116His) is reported the same year.
- 2022 — Independent case reports confirm autosomal recessive inheritance and the rapidly progressive course; one infant is bridged to successful heart transplantation with a Berlin Heart LVAD.
- 2023 — The gene's day job: two landmark studies show Rpl3l-knockout mice are viable through RPL3 compensation, and that RPL3L-containing ribosomes tune translation elongation dynamics required for cardiac contraction.
- 2023 — The first Chinese case expands the allelic spectrum (a novel frameshift variant) and adds arrhythmias and AV block to the phenotype.
- 2026 — The mechanism is solved: Murphy et al. propose the dual loss-/gain-of-function model — hotspot variants block ribosome biogenesis and prevent compensation by RPL3. Further cases reported (Zhang; Mai).
- Next — With your help: a patient registry, functional variant characterization, and preclinical therapeutic exploration.
Our team
The initiative brings together a Columbia University team that discovered the RPL3L–CMD2D link, cares for the patients, solved its mechanism, and is developing treatments — combining expertise in ribosome biology, clinical genetics, pediatric cardiology, and therapeutic development.
Xuebing Wu, PhD
Ribosome biology
Herbert Irving Assistant Professor at Columbia University (Department of Medicine, Cardiology Division — Cardiometabolic Genomics Program, and Department of Systems Biology). His lab decodes how the genome is written and read using RNA-centric functional genomics, CRISPR technologies, and machine learning, and directly studies the RPL3L-containing muscle-specific ribosome and therapies for RPL3L-linked heart disease. Lab website · Faculty profile
Mythily Ganapathi, PhD
Clinical genetics
Associate Professor of Pathology & Cell Biology at Columbia University Irving Medical Center. A human geneticist, she is co-corresponding author of the 2020 study that first linked biallelic RPL3L variants to neonatal dilated cardiomyopathy, and continues to drive the disease's genetic characterization. Faculty profile
Teresa M. Lee, MD, MS
Pediatric cardiology
Assistant Professor of Pediatrics at Columbia University Irving Medical Center; a pediatric cardiologist and clinical geneticist with advanced training in heart failure and transplantation. A physician-scientist funded by the NIH, she focuses on the genetic causes of infantile cardiomyopathy and bridges genetics and cardiology at the bedside. Faculty profile
Barry Fine, MD, PhD
Drug development
Florence Irving Assistant Professor of Medicine in the Division of Cardiology at Columbia University Irving Medical Center and the Esther and Oded Aboodi Scholar. A physician-scientist in cardiogenetics and molecular cardiology, he uses stem cells and engineered human heart tissue for drug and gene therapy discovery, and runs a cardiogenetics clinic involved in experimental gene therapy trials for inherited cardiomyopathies. Faculty profile
Contact & community
The initiative is in formation. If you are a family affected by an RPL3L variant, a clinician caring for such a patient, or a researcher working on muscle-specific ribosomes, we want to hear from you.
The initiative is led by a Columbia University team — Xuebing Wu, Mythily Ganapathi, Teresa M. Lee, and Barry Fine — that discovered the RPL3L–CMD2D link, cares for the patients, solved its mechanism, and is developing treatments (meet the team).
Families Clinicians Researchers