TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Abstract

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

• Authors: Mary C Whitman, Brenda J Barry, Caroline D Robson, Flavia M Facio, Carol Van Ryzin, Wai-Man Chan, Tanya J Lehky, Audrey Thurm, Christopher Zalewski, Kelly A King, Carmen Brewer, Konstantinia Almpani, Janice S Lee, Angela Delaney, Edmond J FitzGibbon, Paul R Lee, Camilo Toro, Scott M Paul, Omar A Abdul-Rahman, Bryn D Webb, Ethylin Wang Jabs, Hans Ulrik Moller, Dorte Ancher Larsen, Jayne H Antony, Christopher Troedson, Alan Ma, Glad Ragnhild, Katrine V Wirgenes, Emma Tham, Malin Kvarnung, Timothy James Maarup, Sarah MacKinnon, David G Hunter, Francis S Collins, Irini Manoli, Elizabeth C Engle
• Journal: Human genetics (Hum Genet) Vol. 140 Issue 12 Pg. 1709-1731 (Dec 2021) ISSN: 1432-1203 [Electronic] Germany
• PMID: 34652576 (Publication Type: Journal Article)
• Copyright: © 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Chemical References

• TUBB3 protein, human
• Tubulin
• Histidine
• Arginine

Topics

• Abnormalities, Multiple (genetics)
• Adolescent
• Adult
• Amino Acid Substitution
• Arginine
• Child
• Child, Preschool
• Facial Paralysis (diagnosis, genetics, physiopathology)
• Female
• Fibrosis (diagnosis, genetics, physiopathology)
• Histidine
• Humans
• Infant
• Male
• Mutation
• Ophthalmoplegia (diagnosis, genetics, physiopathology)
• Peripheral Nervous System Diseases (diagnosis, genetics, physiopathology)
• Syndrome
• Tubulin (genetics)
• Young Adult