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<p>Lobodontia, a rare dental anomaly marked by supernumerary cusps and a single pyramid-shaped molar root, has been previously linked to a variant in the <i>CACNA1S</i> gene without definitive evidence. This study investigates 17 patients with lobodontia from Thai and Croatian families. Microsatellite genotyping defines a 15.4 Mbp critical region encompassing <i>CACNA1S</i> and <i>ASCL5</i>&#xa0;among Thai families. While genome sequencing confirms the <i>CACNA1S</i> variant only in the Thai patients, all 17 patients harbor the <i>ASCL5</i> c.274 G &gt; A (p.Glu92Lys) variant, which is absent in 12 unaffected members. Functional studies using CRISPR/Cas9-generated <i>Ascl5</i> knock-in mutant mice demonstrate the dental anomalies resembling lobodontia in Ascl5<sup>Mut/WT</sup>, while Ascl5<sup>Mut/Mut</sup> display severe defects in tooth and jaw development, underscoring the essential role of <i>ASCL5</i> in craniofacial patterning. Transcriptomic analysis of E17.5 mandibular dental arches reveals differential expression of key craniofacial developmental genes in Ascl5<sup>Mut/Mut</sup> compared to Ascl5<sup>WT/WT</sup>, including <i>Dlx1as</i>, and <i>Dlx2</i>. Luciferase assay shows that the p.Glu92Lys ASCL5 impairs <i>DLX2</i> activation, further supporting the variant’s pathogenicity. This study establishes <i>ASCL5</i> as the gene responsible for lobodontia, revising its previously understood genetic basis, and highlights its crucial role in craniofacial development.</p>

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A missense variant in ASCL5 leads to lobodontia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月12日

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  • Thanakorn Theerapanon,
  • Narin Intarak,
  • Khanti Rattanapornsompong,
  • Sermporn Thaweesapphithak,
  • Kanokwan Sriwattanapong,
  • Sasiprapa Prommanee,
  • Sirinya Kulvitit,
  • Tomislav Skrinjaric,
  • Lakshman Samaranayake,
  • Monnat Pongpanich,
  • Patra Yeetong,
  • Nardtiwa Chaivoravitsakul,
  • Nicole Sirisopit Mehl,
  • Adjima Assawapitaksakul,
  • Chalurmpon Srichomthong,
  • Wanna Chetruengchai,
  • Thantrira Porntaveetus,
  • Vorasuk Shotelersuk

摘要

Lobodontia, a rare dental anomaly marked by supernumerary cusps and a single pyramid-shaped molar root, has been previously linked to a variant in the CACNA1S gene without definitive evidence. This study investigates 17 patients with lobodontia from Thai and Croatian families. Microsatellite genotyping defines a 15.4 Mbp critical region encompassing CACNA1S and ASCL5 among Thai families. While genome sequencing confirms the CACNA1S variant only in the Thai patients, all 17 patients harbor the ASCL5 c.274 G > A (p.Glu92Lys) variant, which is absent in 12 unaffected members. Functional studies using CRISPR/Cas9-generated Ascl5 knock-in mutant mice demonstrate the dental anomalies resembling lobodontia in Ascl5Mut/WT, while Ascl5Mut/Mut display severe defects in tooth and jaw development, underscoring the essential role of ASCL5 in craniofacial patterning. Transcriptomic analysis of E17.5 mandibular dental arches reveals differential expression of key craniofacial developmental genes in Ascl5Mut/Mut compared to Ascl5WT/WT, including Dlx1as, and Dlx2. Luciferase assay shows that the p.Glu92Lys ASCL5 impairs DLX2 activation, further supporting the variant’s pathogenicity. This study establishes ASCL5 as the gene responsible for lobodontia, revising its previously understood genetic basis, and highlights its crucial role in craniofacial development.