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Novel ALDH3A2 mutations in structural and functional domains of FALDH causing diverse clinical phenotypes in Sjögren-Larsson Syndrome patients

Rajeshwari, M; Karthi, S; Reetu, S; Efthymiou, S; Gowda, VK; Varalakshmi, P; Srinivasan, VM; ... Ashokkumar, B; + view all (2021) Novel ALDH3A2 mutations in structural and functional domains of FALDH causing diverse clinical phenotypes in Sjögren-Larsson Syndrome patients. Human Mutation 10.1002/humu.24236. (In press).

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Abstract

Mutations in ALDH3A2 cause Sjögren-Larsson Syndrome (SLS), a neuro-ichthyotic condition that is caused by deficiency of fatty aldehyde dehydrogenase (FALDH). We screened for novel mutations causing SLS among Indian ethnicity, characterized the identified mutations in silico and in vitro; and retrospectively evaluated their role in phenotypic heterogeneity. Interestingly, asymmetric distribution of non-classical traits was observed in our cases. Nerve conduction studies suggested intrinsic-minus-claw hands in two siblings, a novel neurological phenotype to SLS. Genetic testing revealed 5 novel homozygous ALDH3A2 mutations in six cases: Case-1-NM_000382.2:c.50C>A, NP_000373.1:p.(Ser17Ter); Case-2-NM_000382.2:c.199G>T, NP_000373.1:p.(Glu67Ter); Case-3-NM_000382.2:c.1208G>A, NP_000373.1:p.(Gly403Asp); Case-4-NM_000382.2:c.1325C>T, NP_000373.1:p.(Pro442Leu); Case-5&6-NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter). The mutations identified were predicted to be pathogenic and disrupts the functional domains of the FALDH. p.(Pro442Leu) at the C-terminal α-helix, might impair substrate gating process. Mammalian expression studies with exon-9 mutants confirmed the profound reduction in the enzyme activity. Diminished aldehyde oxidizing activity was observed with cases-2&3. Cases-2 & 3 showed epidermal hyperplasia with mild intracellular edema, spongiosis, hypergranulosis, and perivascular-interstitial lymphocytic infiltrate and a leaky eosinophilic epidermis. The presence of keratin-milia like lipid vacuoles implies defective lamellar secretion with p.(Gly403Asp). This study improves our understanding of the clinical and mutational diversity in SLS, which might help to fast-track diagnostic and therapeutic interventions of this debilitating disorder. This article is protected by copyright. All rights reserved.

Type: Article
Title: Novel ALDH3A2 mutations in structural and functional domains of FALDH causing diverse clinical phenotypes in Sjögren-Larsson Syndrome patients
Location: United States
DOI: 10.1002/humu.24236
Publisher version: http://dx.doi.org/10.1002/humu.24236
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions
Keywords: ALDH3A2, Exome sequencing, FALDH, Ichthyosis, Neuro-cutaneous, Sjögren -Larsson Syndrome
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10129391
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