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

Mohan Rajeshwari, Sellamuthu Karthi, Reetu Singh, Stephanie Efthymiou, Vykuntaraju K. Gowda, Perumal Varalakshmi, Varunvenkat M. Srinivasan, Henry Houlden, Markus A. Keller, William B. Rizzo, Balasubramaniem Ashokkumar

Research output: Contribution to journalArticlepeer-review


Mutations in ALDH3A2 cause Sjögren–Larsson syndrome (SLS), a neuro-ichthyotic condition due to the 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 nonclassical 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 five 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 and -6 NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter). The mutations identified were predicted to be pathogenic and disrupt the functional domains of the FALDH. p.(Pro442Leu) at the C-terminal α-helix, might impair the 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 and 3. Cases-2 and 3 showed epidermal hyperplasia with mild intracellular edema, spongiosis, hypergranulosis, and perivascular-interstitial lymphocytic infiltrate and a leaky eosinophilic epidermis. The presence of keratin-containing 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.

Original languageEnglish (US)
Pages (from-to)1015-1029
Number of pages15
JournalHuman mutation
Issue number8
StatePublished - Aug 2021


  • ALDH3A2
  • Sjögren–Larsson syndrome
  • exome sequencing
  • ichthyosis
  • neuro-cutaneous

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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