Sjogren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase (FALDH). The symptoms of SLS include ichthyosis, mental retardation and spasticity, and are hypothesized to arise from the deranged metabolism of fatty aldehydes and precursor lipids such as fatty alcohols, which cannot be metabolized by FALDH. However, little is known about the underlying biochemical pathogenesis of SLS and effective therapy for the disease is lacking. The long-term goal of our research is to understand the pathogenic mechanisms causing the symptoms of SLS in order to develop specific therapy for affected patients. To gain insight into the biochemical and pathologic abnormalities in SLS, we will extensively characterize the biochemical and phenotypic features of a new FALDH-deficient gene knockout mouse model for SLS, and examine the role of genetic background on its phenotypic expression. Cultured keratinocytes, oligodendrocytes and mixed neuronal cells from FALDH-deficient mice will be investigated to reveal cell- specific lipid abnormalities. Using FALDH-deficient mice and cultured cells from SLS patients, we will determine whether FALDH is implicated in the metabolism of fatty aldehydes and fatty alcohols generated from farnesol, w-hydroxy fatty acids and (R)-trioxilin A3. These pathways are potentially amenable to therapeutic intervention with dietary modification and pharmacologic agents. Using immunologic and chemical methods together with mass spectrometry, we will identify the proteins that are covalently modified by fatty aldehyde in SLS cells to gain insight into the pathogenic mechanisms responsible for the cutaneous and neurologic symptoms. In summary, these studies will define the aberrant metabolism in SLS cells arising from FALDH deficiency and take advantage of the first animal model for SLS to uncover new pathogenic mechanisms responsible for cutaneous and neurologic symptoms. This research is directed at investigating Sjogren-Larsson syndrome (SLS), an inherited metabolic disease affecting the skin and brain of children and adults. We will study the abnormal fat metabolism that occurs in skin cells from patients to discover the cause of the symptoms, and characterize a newly developed mouse that has the same metabolic problem as people with SLS in hopes of developing an effective treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044552-15
Application #
7917332
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
1997-04-10
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
15
Fiscal Year
2010
Total Cost
$304,665
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Rizzo, William B (2014) Fatty aldehyde and fatty alcohol metabolism: review and importance for epidermal structure and function. Biochim Biophys Acta 1841:377-89
Davis, Kathleen; Holden, Kenton R; S'Aulis, Dana et al. (2013) Novel mutation in Sjogren-Larsson syndrome is associated with divergent neurologic phenotypes. J Child Neurol 28:1259-65
Rizzo, William B; Jenkens, Sabrina Malone; Boucher, Philip (2012) Recognition and diagnosis of neuro-ichthyotic syndromes. Semin Neurol 32:75-84
Engelstad, Holly; Carney, Gael; S'aulis, Dana et al. (2011) Large contiguous gene deletions in Sjögren-Larsson syndrome. Mol Genet Metab 104:356-61
Rizzo, William B (2011) The role of fatty aldehyde dehydrogenase in epidermal structure and function. Dermatoendocrinol 3:91-9
Milstone, Leonard M; Rizzo, William B; Pickford, Jean R (2011) Meeting report from Frontiers in Ichthyosis Research. J Invest Dermatol 131:279-82
Aldahmesh, Mohammed A; Mohamed, Jawahir Y; Alkuraya, Hisham S et al. (2011) Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet 89:745-50
Rizzo, William B; S'Aulis, Dana; Jennings, M Anitia et al. (2010) Ichthyosis in Sjogren-Larsson syndrome reflects defective barrier function due to abnormal lamellar body structure and secretion. Arch Dermatol Res 302:443-51
Rizzo, William B; Craft, Debra A; Somer, Tara et al. (2008) Abnormal fatty alcohol metabolism in cultured keratinocytes from patients with Sjogren-Larsson syndrome. J Lipid Res 49:410-9
Rizzo, William B (2007) Sjogren-Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency. Mol Genet Metab 90:1-9

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