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. 2024 Jan 10;9(4):a006293.
doi: 10.1101/mcs.a006293. Print 2023 Dec.

De novo TRPM3 missense variant associated with neurodevelopmental delay and manifestations of cerebral palsy

Jagadish Chandrabose Sundaramurthi  1 , Anita M Bagley  2 , Hannah Blau  1 , Leigh Carmody  1 , Amy Crandall  3 , Daniel Danis  1 , Michael A Gargano  1 , Anxhela Gjyshi Gustafson  4 , Ellen M Raney  3 , Mallory Shingle  2 , Jon R Davids  2   5 , Peter N Robinson  6   7
Affiliations

De novo TRPM3 missense variant associated with neurodevelopmental delay and manifestations of cerebral palsy

Jagadish Chandrabose Sundaramurthi et al. Cold Spring Harb Mol Case Stud. .

Abstract

We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease-associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp).

Keywords: absent speech; bilateral convulsive seizures; bilateral talipes equinovarus; broad forehead; deeply set eye; intellectual disability, moderate; language impairment; moderate global developmental delay; thoracic scoliosis; torticollis.

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Figures

Figure 1.
Figure 1.
Trio-based whole-genome sequencing (WGS) revealed a de novo variant in the child, 9-70553042-T-C, that is, NM_001366145.2(TRPM3):c.3376A > G.
Figure 2.
Figure 2.
Illustration of human TRPM3 protein generated with PROTTER (Omasits et al. 2014) from the TRPM3 sequence (Q9HCF6-3, MANE-select sequence version). N1126D is the de novo variant identified in the current case and other previously known variants (listed in Table 2) have been mapped in the transmembrane domain and cytoplasmic domain of the TRPM3. The ion transport domain 891–1133 (residues from 904 to 1146 was on the TRPM3 canonical sequence, UniProt Q9HCF6) highlighted in purple contains seven of the 10 variants (or five of the eight variant positions) identified to date including the variant, N1126D, reported in this study.
Figure 3.
Figure 3.
Three-dimensional structure and molecular interactions in human TRPM3 protein: (A) The TRPM3 protein represented by one chain; (B) homotetramer form of the TRPM3 channel, in a side view showing ion transport domain; (C) the TRPM3 protein from top view. In A–C, the variant position observed in the present study (N1126) is displayed in red; variant positions P1102, V1002, G1007, and S1133 that are present in ion transport domain are shown in cyan; variants from cytoplasmic domain (D614 and L769) are displayed in green color. (D) Corresponding view of the variant protein with Asp1126 shown in orange in one of the four chains along with interacting amino acids highlighted in green and neighboring Asn1125 in blue. The ion transport domain is displayed in magenta in A or four different shades of magenta to represent four chains of TRPM3 in B and pink in C and D.
See this image and copyright information in PMC

References

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