Genetic disorders

Epidermolysis bullosa simplex (EBS)

Epidermolysis bullosa simplex (EBS)

EBS is a rare disease with a prevalence between 1/50,000 to 1/30,000. It is characterized by asymptomatic desquamations of the skin at the basal layer. EBS is inherited through autosomal dominant transmission and can be caused by more than one hundred mutations located in the genes coding for keratin 5 and keratin 14 (KRT5 and KRT14, respectively). Three subtypes of EBS have been characterized: Weber–Cockayne, Koebner, and Dowling-Meara; the latter being the most severe form. The mutations in KRT5 and KRT14 lead to the formation of defective proteins. Those proteins are unable to organize into networks of filaments and aggregates are formed. At present EBS has no cures. Existing treatment only aims at reducing pain and infections.

Biobank

In 2008, Dr. Laprise established a biobank for the research on EBS and it is located at the Univeristé du Québec à Chicoutimi (UQAC). At present the biobank has archived DNA from 9 EBS patients with their age- and sex-matched control subjects. It is the largest collection of its kind in the world. In addition to DNA isolated from whole blood, keratinocytes cell lines of primary and immortalized cells, fibroblasts isolated from skin biopsies, DNA, and RNA are available for research use.

Active research project

Ongoing research projects

  • Homology directed repair of Epidermolysis Bullosa Simplex (EBS) single mutations using induced pluripotent stem cells and CRISPR/Cas9 system (Collaborators: Lucie Germain, Jacques P Tremblay)
  • Evaluation of a treatment using a brown seaweed extract on the formation of K14 aggregates in keratinocytes in EBS (Collaborators: Tarik Farez, Audrey Dupérée, Georgette Leclerc, Charles Morin, Catherine McCuaig, and Julie Powell)

Information website http://www.debra-international.org/epidermolysis-bullosa.html

Agenesis and digenesis of the corpus callosum

Agenesis and digenesis of the corpus callosum

Clinical manifestations of partial or complete agenesis of the corpus callosum, an anormality in the brain structure, vary from asymptomatic to delayed development, hypotonia, epilepsy, and microcephaly. In the SLSJ region, several pediatricians noticed that a number of patients with partial or complete agenesis of the corpus callosum without polyneuropathy have hypotonia and later presented with delayed development, epilepsy and microcephaly. Further characterization of 8 to 12 affected patients by the pediatricians in the region concluded that this phenotype may be (1) a monogenic condition with both autosomal and recessive transmission modes or (2) a complex trait with mulitple causal genes. Whether the condition is monogenic or polygenic, the identification of the causal mutations would be impactful in terms of genetic testing, genetic counciling, and treatment development.

Ongoing research project

  • Genetic association study of agenesis or dysgenesis of the corpus callosum in children with developmental delay, epilepsy, and microcephaly (Collaborators: Vanessa Brunet, Charles Morin and Jean-Benoît Bouchard)

French Canadian Leigh Syndrome

French Canadian Leigh Syndrome

Leigh syndrome French Canadian (LSFC) is a neurodegenerative disorder that belongs to the large family of Leigh syndromes. LSFC patients may have childhood onset of acidosis; hence, it is also called congenital lactic acidosis type SLSJ. In most cases, acidosis occurs in the first 5 years of life and often fatal. In the SLSJ region the disease affects 1/2000 births. The most frequent clinical signs are hypotonia (low muscular tonus), chronic well-compensated metabolic acidosis, and delayed neuromotor development. While most children with LFSC exhibited these clinical signs, the degree of disabilities and severity vary among patients. Such variability is very important and relevant in disease management. For example, some children with LSFC are very active and walk normally while others have severe physical disabilities, limited mobility, and relie on wheelchairs. It is now recognized that LSFC is caused by a mutation in the LRPPRC (Leucin-rich pentatricopeptide repeat containing) gene with the encoded protein implicated in the stability and processing of mature mRNAs. This mutation leads to cytochrome c oxydase (COX) deficiency. COX enzymatic activity has been shown to be reduced in several organs (i.e. liver, brain, muscles, fibroblasts, and kidneys) as compared to normal activity values (Am J Hum Genet. 1993 Aug;53(2):481-7). Unfortunately at present there is no cure for LSFC.

Biobank

The LSFC biobank was established by Dr.Laprise in 2008 and is located at UQAC. This biobank archived biological samples from 21 affected individuals (of whom 7 are from therapeutic pregnancy termination (TPT)), 14 carriers and 23 controls (of whom 3 are from TPT). Fibroblasts isolated from skin biopsies (primary and immortalized), DNA, RNA, and tissues from TPT (e.g. cortez, brain, cerebellum, heart, kidney, liver, muscle, etc) are available to the research members of the LSFC Consortium and to those whose research projects have received scientific and ethics approvals from the consortium. Recruitment is onging and additional samples are being deposited in the biobank each year.

Ongoing research project

  • Methylation profile of genes involved in the respiratory chain functions in case-control study