bims-meglyc 2024-04-07 papers

Issue of 2024–04–07
three papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab Rep. 2024 Jun;39 101072

Novel mutation of COG5 in a Taiwanese girl with congenital disorders of glycosylation manifesting as developmental delay.

Yu-Chi Wang, Dau-Ming Niu, Li-Zhen Chen, Yun-Ru Chen, Chia-Feng Yang.

We are documenting the case of An 11-year-old girl who has been followed up at our out-patient clinic since birth with clinical presentations including intrauterine growth restriction, recurrent periodic fever in infancy, hypotonia, global developmental delay, liver function impairment with cirrhotic changes, and clinodactyly. Congenital abnormalities were suspected but a series of examinations including brain MRI, liver biopsy and muscle biopsy yielded insignificant findings. Whole genome sequencing (WGS) was conducted and revealed three novel mutations (c2T > G, c1826T > C, c.556-560delAGTAAinsCT) of the COG5 gene. A diagnosis of COG5-congenital disorders of glycosylation (COG5-CDG, or CDG IIi), with neurologic presentation was established. Sanger sequencing in the patient and her parents confirmed the compound heterozygous mutation. Upon literature review, we identified the patient as the first case of COG5-CDG in Taiwan. Our study enhances the clarity of the correlation between the mutative genes and the presentation of COG5-CDG.

Keywords: COG5; Congenital disorders of glycosylation; Developmental delay

DOI: https://doi.org/10.1016/j.ymgmr.2024.101072

Dis Model Mech. 2024 Apr 03. pii: dmm.050671. [Epub ahead of print]

Neurodevelopmental defects in a mouse model of O-GlcNAc transferase intellectual disability.

Florence Authier, Nina Ondruskova, Andrew T Ferenbach, Alison McNeilly, Daan M F van Aalten.

O-GlcNAcylation is a protein modification that is critical for vertebrate development, catalysed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense mutations in OGT have recently been shown to segregate with a X-linked syndromic form of intellectual disability, OGT-linked Congenital Disorder of Glycosylation (OGT-CDG). Although OGT-CDG suggests a critical role of O-GlcNAcylation in neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and OGT/OGA levels in the brain. Phenotypic characterization of the mice revealed lower body weight associated with reduced body fat mass, short stature and microcephaly. This mouse model will serve as an important tool to study genotype-phenotype correlation in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder.

Keywords: Cognitive function; Neurodevelopment; Vertebrate development

DOI: https://doi.org/10.1242/dmm.050671

Mol Genet Metab. 2024 Mar 28. pii: S1096-7192(24)00284-1. [Epub ahead of print]142(1): 108469

TRAPPC11-CDG muscular dystrophy: Review of 54 cases including a novel patient.

Jorge Román Corona-Rivera, Iván Martínez-Duncker, Eva Morava, Wasantha Ranatunga, Roberta Salinas-Marin, Ana María González-Jaimes, Katia Alejandra Castillo-Reyes, Christian Peña-Padilla, Lucina Bobadilla-Morales, Alfredo Corona-Rivera, Mireya Orozco-Vela, Sinhue Alejandro Brukman-Jiménez.

The trafficking protein particle (TRAPP) complex is a multisubunit protein complex that functions as a tethering factor involved in intracellular trafficking. TRAPPC11, a crucial subunit of this complex, is associated with pathogenic variants that cause a spectrum of disease, which can range from a limb girdle muscular dystrophy (LGMD) to developmental disability with muscle disease, movement disorder and global developmental delay (GDD)/intellectual disability (ID), or even a congenital muscular dystrophy (CMD). We reviewed the phenotype of all reported individuals with TRAPPC11-opathies, including an additional Mexican patient with novel compound heterozygous missense variants in TRAPPC11 (c.751 T > C and c.1058C > G), restricted to the Latino population. In these 54 patients muscular dystrophy signs are common (early onset muscle weakness, increased serum creatine kinase levels, and dystrophic changes in muscle biopsy). They present two main phenotypes, one with a slowly progressive LGMD with or without GDD/ID (n = 12), and another with systemic involvement characterized by short stature, GDD/ID, microcephaly, hypotonia, poor speech, seizures, cerebral atrophy, cerebellar abnormalities, movement disorder, scoliosis, liver disease, and cataracts (n = 42). In 6 of them CMD was identified. Obstructive hydrocephaly, retrocerebellar cyst, and talipes equinovarus found in the individual reported here has not been described in TRAPPC11 deficiency. As in previous patients, membrane trafficking assays in our patient showed defective abnormal endoplasmic reticulum-Golgi transport as well as decreased expression of LAMP2, and ICAM-1 glycoproteins. This supports previous statements that TRAPPC11-opathies are in fact a congenital disorder of glycosylation (CDG) with muscular dystrophy.

Keywords: CDG; CMD; Congenital muscular dystrophy; Glycosylation; Hydrocephaly; LGMD; Retrocerebellar cyst; Talipes equinovarus

DOI: https://doi.org/10.1016/j.ymgme.2024.108469