Unraveling the complexity of vitamin B12 diseases

Date:
January 10, 2022
Source:
Baylor College of Medicine
Summary:
Researchers unravel the genetic complexity two rare inherited
vitamin B12 conditions identifying them as hybrid syndromes that
are both a vitamin B12 disorder and a disease of ribosomes, the
protein-building machinery of the cell.



FULL STORY ==========================================================================
A team of researchers at Baylor College of Medicine and collaborating institutions has shed new light into the complexity of vitamin B12
diseases.

The scientists studied two rare inherited vitamin B12 conditions that
affect the same gene but are clinically distinct from the most common
genetic vitamin B12disorder. This work suggested that, in addition to
the gene affected in the common vitamin B12 disease, other genes also
were affected, making a more complex syndrome. This study searched for
those genes and their function.


========================================================================== Working with mouse models, the team found that the genes involved in
the more complex forms of the condition not only cause the expected
typical vitamin B12disease but also affect the generation of ribosomes,
the protein-building machinery of the cell. The findings, published in
the journal Nature Communications, support reevaluating how to treat
these patients in the future and have implications for genetic counseling.

"Vitamin B12, or cobalamin, is a dietary nutrient essential for normal
human development and health and is found in animal-based foods but not
in vegetables. Mutations in the genes encoding the proteins responsible
for the metabolic processes involving vitamin B12 result in rare human
inborn errors of cobalamin metabolism," said co-corresponding author
Dr. Ross A. Poche', associate professor of molecular physiology and
biophysics at Baylor.

Patients with the most common inherited vitamin B12 disease, called cblC, suffer from a multisystem disease that can include intrauterine growth restriction, hydrocephalus (the build-up of fluid in the cavities deep
within the brain), severe cognitive impairment, intractable epilepsy,
retinal degeneration, anemia and congenital heart malformations. Previous
work had shown that mutations in the MMACHCgene cause cblC disease.

It also was known that some patients presenting with a combination of
typical and non-typical cblC characteristics do not have mutations in
the MMACHC gene, but rather in genes that code for for proteins called
RONIN (also known as THAP11) and HCFC1. The resulting changes in these
proteins lead to reduced MMACHC gene expression and a more complex
cblC-like disease.

In this study, Poche' and his colleagues looked for other genes that
also might be affected by HCFC1 and RONINgene mutations.



==========================================================================
"We developed mouse models carrying the exact same mutations that
the patients with cblC-like disease have in HCFC1 or RONIN genes, and
recorded the animals' characteristics," Poche' said. "We confirmed that
they presented with the cobalamin syndrome as expected, but in addition
we found that they had ribosome defects. This is the first time that
the HCFC1 and RONIN genes have been identified as regulators of ribosome biogenesis during development." The researchers demonstrate that this cblC-like disease affecting the function of RONIN and HCFC1 proteins is
a hybrid syndrome as it is both a cobalamin disorder and a disease of ribosomes, or a ribosomopathy.

The findings have potential therapeutic implications. "Some cblC-like
patients may respond to some extent to cobalamin supplementation, but
we anticipate that will not help the issues due to ribosome defects,"
said Poche', member of the Dan L Duncan Comprehensive Cancer Center.

One step toward designing effective ribosomopathy therapies is to
better understand what the defects in the ribosomes are. "We plan to functionally characterize the altered ribosomes at the molecular level
to identify how their function is disrupted," Poche' said.

"There are many exciting aspects of this study, from the clinical
implications to the basic science. The beauty is in how the work in
patients is symbiotic with the work in the mouse model and how each
system informs the other," said co-author Dr. David S. Rosenblatt,
professor in the departments of human genetics, medicine, pediatrics,
and biology at McGill University and senior scientist at the Research
Institute of the McGill University Health Centre.

Other contributors to this work include co-first authors Tiffany Chern
and Annita Achilleos, Xuefei Tong, Matthew C. Hill, Alexander B. Saltzman, Lucas C.

Reineke, Arindam Chaudhury, Swapan K. Dasgupta, Yushi Redhead, David
Watkins, Joel R. Neilson, Perumal Thiagarajan, Jeremy B. A. Green,
Anna Malovannaya and James F. Martin. The authors are affiliated with
one or more of the following institutions: Baylor College of Medicine; University of Nicosia Medical School, Cyprus; Michael E. DeBakey Veterans Affairs Medical Center, Houston; the Francis Crick Institute, London;
King's College London; McGill University Health Centre, Montreal and
Texas Heart Institute, Houston.

This work was supported by the Dan L Duncan Comprehensive Cancer
Center's National Institutes of Health (NIH) award P30CA125123 for BCM
Mass Spectrometry Proteomics Core, CPRIT Core Facility Award (RP170005)
and the following NIH grants: R01 EY024906, R01 DE028298, T32 EY007102,
T32 HL007676, R01 HL127717, R01 HL130804 and R01HL118761. Additional
support was provided by the Vivian L.

Smith Foundation, State of Texas funding and Foundation LeDucq
Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01).

========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Graciela Gutierrez. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Tiffany Chern, Annita Achilleos, Xuefei Tong, Matthew C. Hill,
Alexander
B. Saltzman, Lucas C. Reineke, Arindam Chaudhury, Swapan
K. Dasgupta, Yushi Redhead, David Watkins, Joel R. Neilson, Perumal
Thiagarajan, Jeremy B. A. Green, Anna Malovannaya, James F. Martin,
David S.

Rosenblatt, Ross A. Poch�. Mutations in Hcfc1 and Ronin
result in an inborn error of cobalamin metabolism and ribosomopathy.

Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-021-27759-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220110103240.htm
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