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A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology.

ABSTRACT: The Rac1 guanine exchange factor Kalirin-7 is a key regulator of dendritic spine morphology, LTP and dendritic arborization. Kalirin-7 dysfunction and genetic variation has been extensively linked to various neurodevelopmental and neurodegenerative disorders. Here we characterize a Kalirin-7 missense mutation, glu1577lys (E1577K), identified in a patient with severe developmental delay. The E1577K point mutation is located within the catalytic domain of Kalirin-7, and results in a robust reduction in Kalirin-7 Rac1 Guanosine exchange factor activity. In contrast to wild type Kalirin-7, the E1577K mutant failed to drive dendritic arborization, spine density, NMDAr targeting to, and activity within, spines. Together these results indicate that reduced Rac1-GEF activity as result of E1577K mutation impairs neuroarchitecture, connectivity and NMDAr activity, and is a likely contributor to impaired neurodevelopment in a patient with developmental delay.

SUBMITTER: Parnell E

PROVIDER: S-EPMC9751355 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology.

Parnell Euan E Voorn Roos A RA Martin-de-Saavedra M Dolores MD Loizzo Daniel D DD Dos Santos Marc M Penzes Peter P

Frontiers in molecular neuroscience 20221201

The Rac1 guanine exchange factor Kalirin-7 is a key regulator of dendritic spine morphology, LTP and dendritic arborization. Kalirin-7 dysfunction and genetic variation has been extensively linked to various neurodevelopmental and neurodegenerative disorders. Here we characterize a Kalirin-7 missense mutation, glu1577lys (E1577K), identified in a patient with severe developmental delay. The E1577K point mutation is located within the catalytic domain of Kalirin-7, and results in a robust reducti ...[more]

PMID: 36533124

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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.

Project description:BackgroundThe diaphragm is the primary muscle of inspiration, and its dysfunction is frequent during sepsis. However, the mechanisms associated with sepsis and diaphragm dysfunction are not well understood. In this study, we evaluated the morphophysiological changes of the mitochondrial diaphragm 5 days after sepsis induction.MethodsMale C57Bl/6 mice were divided into two groups, namely, cecal ligation and puncture (CLP, n = 26) and sham-operated (n = 19). Mice received antibiotic treatment 8 h after surgery and then every 24 h until 5 days after surgery when mice were euthanized and the diaphragms were collected. Also, diaphragm function was evaluated in vivo by ultrasound 120 h after CLP. The tissue fiber profile was evaluated by the expression of myosin heavy chain and SERCA gene by qPCR and myosin protein by using Western blot. The Myod1 and Myog expressions were evaluated by using qPCR. Diaphragm ultrastructure was assessed by electron microscopy, and mitochondrial physiology was investigated by high-resolution respirometry, Western blot, and qPCR.ResultsCecal ligation and puncture mice developed moderated sepsis, with a 74% survivor rate at 120 h. The diaphragm mass did not change in CLP mice compared with control, but we observed sarcomeric disorganization and increased muscle thickness (38%) during inspiration and expiration (21%). Septic diaphragm showed a reduction in fiber myosin type I and IIb mRNA expression by 50% but an increase in MyHC I and IIb protein levels compared with the sham mice. Total and healthy mitochondria were reduced by 30% in septic mice, which may be associated with a 50% decrease in Ppargc1a (encoding PGC1a) and Opa1 (mitochondria fusion marker) expressions in the septic diaphragm. The small and non-functional OPA1 isoform also increased 70% in the septic diaphragm. These data suggest an imbalance in mitochondrial function. In fact, we observed downregulation of all respiratory chain complexes mRNA expression, decreased complex III and IV protein levels, and reduced oxygen consumption associated with ADP phosphorylation (36%) in CLP mice. Additionally, the septic diaphragm increased proton leak and downregulated Sod2 by 70%.ConclusionThe current model of sepsis induced diaphragm morphological changes, increased mitochondrial damage, and induced functional impairment. Thus, diaphragm damage during sepsis seems to be associated with mitochondrial dysfunction.

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A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology.

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A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology.

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