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Macrocephaly and developmental delay caused by missense variants in RAB5C.

ABSTRACT: Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway.

SUBMITTER: Koop K

PROVIDER: S-EPMC10586195 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Macrocephaly and developmental delay caused by missense variants in RAB5C.

Koop Klaas K Yuan Weimin W Tessadori Federico F Rodriguez-Polanco Wilmer R WR Grubbs Jeremy J Zhang Bo B Osmond Matt M Graham Gail G Sawyer Sarah S Conboy Erin E Vetrini Francesco F Treat Kayla K Płoski Rafal R Pienkowski Victor Murcia VM Kłosowska Anna A Fieg Elizabeth E Krier Joel J Mallebranche Coralie C Alban Ziegler Z Aldinger Kimberly A KA Ritter Deborah D Macnamara Ellen E Sullivan Bonnie B Herriges John J Alaimo Joseph T JT Helbig Catherine C Ellis Colin A CA van Eyk Clare C Gecz Jozef J Farrugia Daniel D Osei-Owusu Ikeoluwa I Adès Lesley L van den Boogaard Marie-Jose MJ Fuchs Sabine S Bakker Jeroen J Duran Karen K Dawson Zachary D ZD Lindsey Anika A Huang Huiyan H Baldridge Dustin D Silverman Gary A GA Grant Barth D BD Raizen David D van Haaften Gijs G Pak Stephen C SC Rehmann Holger H Schedl Tim T van Hasselt Peter P

Human molecular genetics 20231001 21

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparent ...[more]

PMID: 37552066

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Project description:BackgroundThe DYNC1H1 gene encodes a part of the dynamic protein, and the protein mutations may further affect the growth and development of neurons, resulting in degeneration of anterior horn cells of the spinal cord, and a variety of clinical phenotypes finally resulting in axonal Charcot-Marie-Tooth disease type 20 (CMT20), mental retardation 13 (MRD13) and spinal muscular atrophy with lower extremity predominant 1 (SMA-LED). The incidence of the disease is low, and it is difficult to diagnose, especially in children. Here, we report a case of DYNC1H1 gene mutation and review the related literature to improve the pediatrician's understanding of DYNC1H1 gene-related disease to make an early correct diagnosis and provide better services for children.Case summaryA 4-mo-old Chinese female child with adducted thumbs, high arch feet, and epileptic seizure presented slow response, delayed development, and low limb muscle strength. Electroencephalogram showed abnormal waves, a large number of multifocal sharp waves, sharp slow waves, and multiple spasms with a series of attacks. High-throughput sequencing and Sanger sequencing identified a heterozygous mutation, c.5885G>A (p.R1962H), in the DYNC1H1 gene (NM_001376) of the proband, which was not identified in her parents. Combined with the clinical manifestations and pedigree of this family, this mutation is likely pathogenic based on the American Academy of Medical Genetics and Genomics guidelines. The child was followed when she was 1 year and 2 mo old. The magnetic resonance imaging result was consistent with the findings of white matter myelinated dysplasia and congenital giant gyrus. The extensive neurogenic damage to the extremities was considered, as the results of electromyography showed that the motor conduction velocity and sensory conduction of the nerves of the extremities were not abnormal, and the degree of fit of the children with severe contraction was poor. At present, the child is 80 cm in length and 9 kg in weight, with slender limbs and low muscle strength, and still does not raise her head. She cannot sit or speak. Speech, motor, and mental development was significantly delayed. There is still no effective treatment for this disease.ConclusionWe herein report a de novo variant of DYNC1H1 gene, c.5885G>A (p.R1962H), leading to overlapping phenotypes (seizure, general growth retardation, and muscle weakness) of CMT20, MRD13, and SMA-LED, but there is no effective treatment for such condition. Our case enriches the DYNC1H1 gene mutation spectrum and provides an important basis for clinical diagnosis and treatment and genetic counseling.

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Macrocephaly and developmental delay caused by missense variants in RAB5C.

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Macrocephaly and developmental delay caused by missense variants in RAB5C.

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