Johanna Rommens

Last updated
Johanna Rommens
NationalityCanadian
Alma mater University of New Brunswick
Known fordiscovery of genes responsible for cystic fibrosis and Shwachman-Diamond syndrome
Scientific career
Fieldsmolecular genetics
InstitutionsHospital for Sick Children, SickKids Research Institute, University of Toronto
Thesis  (1986)
Academic advisors Lap-Chee Tsui

Johanna Rommens is a Canadian geneticist who was on the research team which identified and cloned the CFTR gene, which when mutated, is responsible for causing cystic fibrosis (CF). She later discovered the gene responsible for Shwachman-Diamond syndrome, a rare genetic disorder that causes pancreatic and hematologic problems. [1] She is a Senior Scientist Emeritus at SickKids Research Institute and a professor in the Department of Molecular Genetics at the University of Toronto. [2]

Contents

Early life and education

Rommens grew up on a farm in eastern New Brunswick, Canada. [3] She earned both her bachelor's degree and a PhD in molecular biology from the University of New Brunswick in Fredericton. [3] She was awarded a Beaverbrook Scholarship for her undergraduate education, [4] and she earned a dual undergraduate degree in biology and organic chemistry. [2] During her graduate education she studied synthetic chemistry in addition to molecular biology, and she received her PhD in 1986. [3] In 1986, she started post-doctoral training in the lab of Lap-Chee Tsui at the Hospital for Sick Children in Toronto, Canada (commonly referred to as SickKids). [5]

Career

Rommens became a senior scientist at the Hospital for Sick Children in Toronto, Canada and a professor at the University of Toronto. [2]

Research

Rommens helped identify the gene behind cystic fibrosis, the CFTR gene (short for cystic fibrosis transmembrane conductance regulator), which was found to be an ion channel. This work was carried out when she was a postdoctoral fellow in the lab of Lap-Chee Tsui at the Hospital for Sick Children (SickKids) in Toronto, Canada, and was a collaboration between Tsui's lab, including fellow postdoctoral researcher Batsheva Kerem, and a team of researchers led by Francis Collins at the University of Michigan. [6] The CFTR gene was discovered through genetic linkage analysis involving looking for genetic markers that were present in patients with cystic fibrosis but not present in their non-affected relatives. Due to the phenomenon of recombination, whereby parts of chromosomes swap homologous segments during germ cell development, each chromosome a child inherits is a mix of the both of that parent's copies of that chromosome. Markers would only be consistently co-inherited with the gene behind cystic fibrosis if they were close together on the chromosome, so Rommens and other researchers used markers to find the approximate location of the gene. [5] They then used a combination of chromosome walking and chromosome hopping or jumping to locate the CF gene, which they named cystic fibrosis transmembrane conductance regulator (CFTR). [6]

Rommens' work on cystic fibrosis didn't stop after she helped identify the CFTR gene. Instead, she continued to research CF once she started her own lab, using her molecular genetics expertise to look outside of the CFTR gene for insight into CF. She helped lead research to discover genetic modifiers of CF - versions of genes other than CFTR that either worsen or ameliorate the effects of CFTR mutations. Such modifiers could help explain why patients with the same CFTR mutations can have differing disease severity. [7] For example, around 15 percent of CF patients are born with an intestinal obstruction called meconium ileus, and, by analyzing genomes from almost 4,000 CF patients, Rommens' team found genetic risk factors associated with developing meconium ileus and lung problems. [8] [9] In addition to using genetics to investigate how multiple genes contribute to CF pathology, she used mouse models to study how mutations in the CFTR gene affect multiple organ systems. [10]

Rommens also investigated the causes of other genetic diseases, chiefly Shwachman-Diamond syndrome (SDS), a rare autosomal recessive genetic disorder that causes pancreatic and hematologic problems. It presents with some of the same symptoms as CF and, after CF, SDS Is the second most common cause of pancreatic insufficiency in children. [11] The pancreas is responsible for producing many digestive enzymes and problems with the pancreas in SDS patients prevent sufficient amounts of these enzymes from reaching the intestines, leading to malabsorption of nutrients. [12] Among other symptoms, the disease often presents with digestive problems, skeletal abnormalities, and frequent infections. [11] In 2002, Rommens discovered that SDS is caused by mutations in the SBDS gene. [1] In addition to the SBDS gene, humans have an SBDS pseudogene (SBDSP), a copy of the SBDS gene which arose via a genetic duplication event, then became inactivated through genetic mutations. [13] Rommens found that patients with SDS had segments of their normal SBDS genes swapped out for the corresponding (mutated) segments of the pseudogene. [1] The most common of the mutations they discovered introduced premature stop codons (PTCs) which led the patients to produce truncated versions of the SBDS protein. [14] This gene was uncharacterized at the time, but Rommens' lab and others would go on to show that, among other potential functions, SBDS is involved in ribosomal maturation. [15] Ribosomes are cellular protein-making complexes, so problems with SBDS could lead to problems with protein synthesis. [15] Rommens helped educate families affected with SDS at a weeklong volunteer-run camp called Camp Sunshine in Casco, Maine. [3]

Rommens also discovered genes implicated in breast and prostate cancer, as well as Alzheimer's disease. [3] She was involved in genetic research on the neurodegenerative disease Huntington's disease as well as Wilson's disease, a copper storage disorder. [4]

Key publications

Related Research Articles

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

<span class="mw-page-title-main">Cystic fibrosis</span> Autosomal recessive disease mostly affecting the lungs

Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males. Different people may have different degrees of symptoms.

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in leading to a truncated, incomplete, and nonfunctional protein product. Nonsense mutation is not always harmful, the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected. As nonsense mutations leads to premature termination of polypeptide chains; they are also called chain termination mutations.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

<span class="mw-page-title-main">Cystic fibrosis transmembrane conductance regulator</span> Mammalian protein found in Homo sapiens

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene.

Forward genetics is a molecular genetics approach of determining the genetic basis responsible for a phenotype. Forward genetics provides an unbiased approach because it relies heavily on identifying the genes or genetic factors that cause a particular phenotype or trait of interest.

Congenital absence of the vas deferens (CAVD) is a condition in which the vasa deferentia reproductive organs fail to form properly prior to birth. It may either be unilateral (CUAVD) or bilateral (CBAVD).

Pancreatic diseases are diseases that affect the pancreas, an organ in most vertebrates and in humans and other mammals located in the abdomen. The pancreas plays a role in the digestive and endocrine system, producing enzymes which aid the digestion process and the hormone insulin, which regulates blood sugar levels. The most common pancreatic disease is pancreatitis, an inflammation of the pancreas which could come in acute or chronic form. Other pancreatic diseases include diabetes mellitus, exocrine pancreatic insufficiency, cystic fibrosis, pseudocysts, cysts, congenital malformations, tumors including pancreatic cancer, and hemosuccus pancreaticus.

<span class="mw-page-title-main">SBDS</span> Protein-coding gene in the species Homo sapiens

Ribosome maturation protein SBDS is a protein that in humans is encoded by the SBDS gene. An alternative transcript has been described, but its biological nature has not been determined. This gene has a closely linked pseudogene that is distally located. This gene encodes a member of a highly conserved protein family that exists from archaea to vertebrates and plants.

The Centre for Applied Genomics is a genome centre in the Research Institute of The Hospital for Sick Children, and is affiliated with the University of Toronto. TCAG also operates as a Science and Technology Innovation Centre of Genome Canada, with an emphasis on next-generation sequencing (NGS) and bioinformatics support. Research at TCAG focuses on the genetic and genomic basis of human variability, health and disease, including research on the genetics of autism spectrum disorder and structural variation of the human genome. The centre is located in the Peter Gilgan Centre for Research and Learning in downtown Toronto, Canada.

Genetic heterogeneity occurs through the production of single or similar phenotypes through different genetic mechanisms. There are two types of genetic heterogeneity: allelic heterogeneity, which occurs when a similar phenotype is produced by different alleles within the same gene; and locus heterogeneity, which occurs when a similar phenotype is produced by mutations at different loci.

A Finnish heritage disease is a genetic disease or disorder that is significantly more common in people whose ancestors were ethnic Finns, natives of Finland and Northern Sweden (Meänmaa) and Northwest Russia. There are 36 rare diseases regarded as Finnish heritage diseases. The diseases are not restricted to Finns; they are genetic diseases with far wider distribution in the world, but due to founder effects and genetic isolation they are more common in Finns.

<span class="mw-page-title-main">Shwachman–Diamond syndrome</span> Medical condition

Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal and cardiac abnormalities and short stature. After cystic fibrosis (CF), it is the second most common cause of exocrine pancreatic insufficiency in children. It is associated with the SBDS gene and has autosomal recessive inheritance.

Ribosomopathies are diseases caused by abnormalities in the structure or function of ribosomal component proteins or rRNA genes, or other genes whose products are involved in ribosome biogenesis.

A human disease modifier gene is a modifier gene that alters expression of a human gene at another locus that in turn causes a genetic disease. Whereas medical genetics has tended to distinguish between monogenic traits, governed by simple, Mendelian inheritance, and quantitative traits, with cumulative, multifactorial causes, increasing evidence suggests that human diseases exist on a continuous spectrum between the two.

Robert Williamson is a retired British-Australian molecular biologist who specialised in the mapping, gene identification, and diagnosis of human genetic disorders.

Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta (US) and Kaftrio (EU), is a fixed-dose combination medication used to treat cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.

Batsheva Kerem, is an Israeli geneticist who was on the research team that identified and cloned the CFTR gene, which when mutated, is responsible for causing cystic fibrosis (CF). She later established the Israel National Center for CF Genetic Research. She discovered the most prevalent cystic fibrosis-causing mutations among the Israeli population, allowing for the establishment of nationwide genetic screening programs to identify carriers of these mutations and enabling prenatal diagnoses. She researches how some CF mutations prevent CFTR protein production by causing nonsense-mediated decay and abnormal mRNA splicing, and how therapies might be able to counteract those problems. She also studies the role of genetic instability in cancer. She is currently a professor at the Hebrew University.

<span class="mw-page-title-main">Cystic fibrosis and race</span>

Underrepresented populations, especially black and hispanic populations with cystic fibrosis are often not successfully diagnosed. This is in part due to the minimal dissemination of existing data on patients from these underrepresented groups. While white populations do appear to experience a higher frequency of cystic fibrosis, other ethnicities are also affected and not always by the same biological mechanisms. Thus, many healthcare and treatment options are less reliable or unavailable to underrepresented populations. This issue affects the level at which public health needs are being met across the world.

<span class="mw-page-title-main">Isolated hyperchlorhidrosis</span> Medical condition

Isolated hyperchlorhidrosis, also known as Carbonic anhydrase XII deficiency, is a rare autosomal recessive genetic condition characterized by a lifelong tendency to lose massive amounts of sodium and chloride through sweat which leads to various symptoms.

References

  1. 1 2 3 "Sick Kids researchers identify gene for Shwachman-Diamond syndrome". EurekAlert!. Retrieved 2021-01-09.
  2. 1 2 3 uoftmedgen (2020-04-17). "Primer Walking to Personal Medicine: A shift in Medical Genomics". The MedGen Project. Retrieved 2021-01-09.
  3. 1 2 3 4 5 "Lifeside up | UNB". www.unb.ca. Retrieved 2021-01-09.
  4. 1 2 "Celebrating 100 years of Beaverbrook Scholars". www.unb.ca. Retrieved 2021-01-16.
  5. 1 2 Trivedi, Bijal P., 1970- (2020). Breath from salt : a deadly genetic disease, a new era in science, and the patients and families who changed medicine forever. Dallas, TX. ISBN   978-1-948836-37-1. OCLC   1083824294.{{cite book}}: CS1 maint: multiple names: authors list (link)
  6. 1 2 Marx, J. L. (1989-09-01). "The cystic fibrosis gene is found". Science. 245 (4921): 923–925. Bibcode:1989Sci...245..923M. doi:10.1126/science.2772644. ISSN   0036-8075. PMID   2772644.
  7. ↑ Moore, Charles. "International Research Consortium Identifies Five Genetic Regions Implicated In Cystic Fibrosis Severity" . Retrieved 2021-01-09.
  8. ↑ "SickKids-led study identifies multiple genes linked to differences in cystic fibrosis". EurekAlert!. Retrieved 2021-01-09.
  9. ↑ Sun, Lei; Rommens, Johanna M.; Corvol, Harriet; Li, Weili; Li, Xin; Chiang, Theodore A.; Lin, Fan; Dorfman, Ruslan; Busson, Pierre-François; Parekh, Rashmi V.; Zelenika, Diana (April 2012). "Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis". Nature Genetics. 44 (5): 562–569. doi:10.1038/ng.2221. ISSN   1546-1718. PMC   3371103 . PMID   22466613.
  10. ↑ "Molecular Medicine and Human Genetics". Molecular Genetics - University of Toronto. Retrieved 2021-01-09.
  11. 1 2 "Shwachman-Diamond Syndrome: Practice Essentials, Pathophysiology, Epidemiology". 2020-12-08.{{cite journal}}: Cite journal requires |journal= (help)
  12. ↑ "Shwachman Diamond Syndrome". NORD (National Organization for Rare Disorders). Retrieved 2021-01-16.
  13. ↑ Whitcomb, David C. (2003-11-01). "The genetics of Shwachman-Diamond syndrome". Gastroenterology. 125 (5): 1541–1543. doi: 10.1016/j.gastro.2003.04.007 . ISSN   0016-5085. PMID   14598273.
  14. ↑ Boocock, Graeme R. B.; Morrison, Jodi A.; Popovic, Maja; Richards, Nicole; Ellis, Lynda; Durie, Peter R.; Rommens, Johanna M. (January 2003). "Mutations in SBDS are associated with Shwachman-Diamond syndrome". Nature Genetics. 33 (1): 97–101. doi:10.1038/ng1062. ISSN   1061-4036. PMID   12496757. S2CID   5091627.
  15. 1 2 "Defective ribosome assembly in Shwachman-Diamond syndrome". Fred Hutch. 2012-12-16. Retrieved 2021-01-22.
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