Sjögren–Larsson syndrome: Novel mutations in the ALDH3A2 gene in a French cohort

Sarret, Catherine; Rigal, Mélanie; Vaurs‐Barrière, Catherine; Dorboz, Imen; Eymard-Pierre, Éléonore; Combes, Patricia; Giraud, G; Wanders, Ronald J. A.; Afenjar, Alexandra; Francannet, Christine; Boespflug‐Tanguy, Odile

doi:10.1016/j.jns.2011.08.006

Cited by 7 publications

(6 citation statements)

References 11 publications

(26 reference statements)

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“…Several publications provided information about the residual enzymatic activity associated with the respective SLS variant (Carney, Wei, & Rizzo, ; Davis et al., ; De Laurenzi et al., ; Didona et al., ; Kariminejad et al., ; Köhler et al., ; Rizzo et al., ; Sarret et al., ; Tsukamoto et al., ; Willemsen et al., ). In essence, two approaches were used to determine enzymatic activity of FALDH: either quantification in cultured cells from patients (predominantly fibroblasts), or over‐expression of mutant FALDH in mammalian, insect, or bacterial cells.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, eight publications were excluded because of probable patient double counts or other specific reasons (prenatally diagnosed patients, etc.). In total, 50 publications contained relevant genetic data and qualified for inclusion in this study (Alió, Bird, McClellan, & Cunningham, ; Aoki, Suzuki, Ito, & Ito, ; Auada et al., ; Botelho Gomes et al., ; Burgueño‐Montañés, Garcia‐Fernández, Colunga‐Cueva, & Garcia‐López, ; Carney et al., ; Cubo & Goetz, ; Davis et al., ; De Laurenzi et al., ; Didona et al., ; Engelstad et al., ; Gaboon, Jelani, Almramhi, Mohamoud, & Al‐Aama, ; Gånemo et al., ; Garcia‐Peris, Latour‐Álvarez, Pestana‐Eliche, & Sánchez, ; Hidalgo et al., ; Incecık, Herguner, Rizzo, & Altunbasak, , ; Jain et al., ; Jean‐François, Low, Gonzales, & Sarraf, ; Kariminejad et al., ; Kim et al., ; Kraus et al., ; Lossos et al., ; Möhrenschlager, Braun‐Falco, & Ring, ; Nagappa et al., ; Nakajima et al, ; Nakano et al., ; Paiva et al., ; Papathemeli et al., ; Rafai et al., ; Rizzo et al., , ; Sakai et al., , ; Sanabria & Coco, ; Sarret et al., ; Shah et al., ; Shamriz, Molho‐Pessach, Shaag, Daum, & Stepensky, ; Shibaki, Akiyama, & Shimizu, ; Sijens et al., ; Sillén et al., ; Tachibana, Aida, Enomoto, Iai, & Kurosawa, ; Taghdiri, Kashef, Fardaei, & Miryounesi, ; Takeichi et al., ; Tanteles et al., ; Tavasoli et al., ; Tsukamoto, Chang, & Yoshida, ; Vural et al., ; Willemsen et al., ; Yiş and Terrinoni, ). One further yet unpublished case has been included into the database. Data extraction : Most of the selected publications contained both, genetic and phenotypic/other information, which was categorized into three groups: …”

Section: Methodsmentioning

confidence: 99%

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Genotype and phenotype variability in Sjögren-Larsson syndrome

et al. 2018

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The Sjögren–Larsson syndrome (SLS) is a rare autosomal recessive disorder caused by pathogenic variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). FALDH prevents the accumulation of toxic fatty aldehydes by converting them into fatty acids. Pathogenic ALDH3A2 variants cause symptoms such as ichthyosis, spasticity, intellectual disability, and a wide range of less common clinical features. Interpreting patient‐to‐patient variability is often complicated by inconsistent reporting and negatively impacts on establishing robust criteria to measure the success of SLS treatments. Thus, with this study, patient‐centered literature data was merged into a concise genotype‐based, open‐access database ( www.LOVD.nl/ALDH3A2 ). One hundred and seventy eight individuals with 90 unique SLS‐causing variants were included with phenotypic data being available for more than 90%. While the three lead symptoms did occur in almost all cases, more heterogeneity was observed for other frequent clinical manifestations of SLS. However, a stringent genotype–phenotype correlation analysis was hampered by the considerable variability in reporting phenotypic features. Consequently, we compiled a set of recommendations of how to generate comprehensive SLS patient descriptions in the future. This will be of benefit on multiple levels, for example, in clinical diagnosis, basic research, and the development of novel treatment options for SLS.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Genotype and phenotype variability in Sjögren-Larsson syndrome

et al. 2018

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“…reviewed 72 different mutations of the ALDH3A2 gene associated with SLS. Since then a series of novel mutations have been reported525354555657585960616263. These include missense mutations (40.9%), deletions (25%), splice site mutations (13.6%), insertion (10.2%), nonsense mutations (6.8%) and some complex mutations (4.5%), which are likely to compromise production of the active FALDH protein.…”

Section: Discussionmentioning

confidence: 99%

A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase

et al. 2014

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Mutations in the gene coding for membrane-bound fatty aldehyde dehydrogenase (FALDH) lead to toxic accumulation of lipid species and development of the Sjögren–Larsson Syndrome (SLS), a rare disorder characterized by skin defects and mental retardation. Here, we present the crystallographic structure of human FALDH, the first model of a membrane-associated aldehyde dehydrogenase. The dimeric FALDH displays a previously unrecognized element in its C-terminal region, a ‘gatekeeper’ helix, which extends over the adjacent subunit, controlling the access to the substrate cavity and helping orientate both substrate cavities towards the membrane surface for efficient substrate transit between membranes and catalytic site. Activity assays demonstrate that the gatekeeper helix is important for directing the substrate specificity of FALDH towards long-chain fatty aldehydes. The gatekeeper feature is conserved across membrane-associated aldehyde dehydrogenases. Finally, we provide insight into the previously elusive molecular basis of SLS-causing mutations.

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“…The size of exon 10 has been curtailed to one-tenth (Continues) effects. 29,39 Although SLS is also reported in Asia, genetic evidence is often not provided.…”

Section: Diagnosismentioning

confidence: 99%

“…The rarity of reports in East Asia could be related to cultural prohibition of consanguineous marriage. Mutation analysis has revealed some region‐specific mutations in Europe and the Middle East, due to consanguineous marriage but also to founder effects . Although SLS is also reported in Asia, genetic evidence is often not provided.…”

Section: Diagnosismentioning

confidence: 99%

Clinical, biochemical, and genetic aspects of Sjögren‐Larsson syndrome

2017

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Sjögren-Larsson syndrome (SLS) is caused by an autosomal recessive mutation in ALDH3A2, which encodes the fatty aldehyde dehydrogenase responsible for the metabolism of long-chain aliphatic aldehydes and alcohols. The pathophysiologic accumulation of aldehydes in various organs, including the skin, brain, and eyes, leads to characteristic features of ichthyosis, intellectual disability, spastic di-/quadriplegia, and low visual acuity with photophobia. The severity of the clinical manifestations thereof can vary greatly, although most patients are bound to a wheelchair due to contractures. To date, correlations between genotype and phenotype have proven difficult to document due to low disease incidence and high heterogenetic variability in mutations. This review summarizes the clinical characteristics of SLS that have been found to contribute to the prognosis thereof, as well as recent updates from genetic and brain imaging studies. In addition, the differential diagnoses of SLS are briefly illustrated, covering cerebral palsy and other genetic or neurocutaneous syndromes mimicking the syndrome.

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Sjögren–Larsson syndrome: Novel mutations in the ALDH3A2 gene in a French cohort

Cited by 7 publications

References 11 publications

Genotype and phenotype variability in Sjögren-Larsson syndrome

Genotype and phenotype variability in Sjögren-Larsson syndrome

A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase

Clinical, biochemical, and genetic aspects of Sjögren‐Larsson syndrome

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