NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy

Çağlayan, Ahmet Okay; Çomu, Sinan; Baranoski, Jacob F; Parman, Yeşim; Kaymakçalan, Hande; Akgumus, Gozde; Çağlar, Caner; Dölen, Duygu; Erson‐Omay, E. Zeynep; Harmancı, Akdes Serin; Mishra-Gorur, Ketu; Freeze, Hudson H.; Yasuno, Katsuhito; Bilgüvar, Kaya; Günel, Murat

doi:10.1016/j.ejmg.2014.08.008

Cited by 72 publications

(89 citation statements)

References 15 publications

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“…Our patient and another described by Caglayan et al [2014] had fractures and osteopenia. There are several potential factors for osteopenia including immobility, hypotonia, muscle atrophy, peripheral neuropathy, and antiepileptic medications.…”

Section: Discussionsupporting

confidence: 46%

“…While this manuscript was in review, a paper was published describing two additional siblings with intellectual disability, neuromotor impairment, neuropathy, and corneal opacities caused by a novel homozygous frame-shift mutation, p.Asn511LysfsX51, in NGLY1 [Caglayan et al, 2014]. This report describes an additional patient with NGLY1-related disorder and compares his findings with reported cases (Table I).…”

Section: Discussionmentioning

confidence: 89%

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Multi‐systemic involvement in NGLY1‐related disorder caused by two novel mutations

Heeley

Shinawi

2015

American J of Med Genetics Pt A

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NGLY1-related disorder is a newly described autosomal recessive condition characterized by neurological, hepatic, ophthalmological findings and associated with dysmorphic features, constipation and scoliosis. It is caused by mutations in NGLY1, which encodes an enzyme, N-glycanase 1, involved in deglycosylation of glycoproteins, an essential step in the endoplasmic reticulum-associated degradation (ERAD) pathway. The disorder has been described in eight patients. We investigated the molecular basis and phenotype of NGLY1-related disorder in an additional patient. The proband is a 14-year-old who presented in early infancy with profound hypotonia and elevated transaminases. Liver biopsy showed lipid accumulation with dilated endoplasmic reticulum. He exhibited global developmental delay, acquired microcephaly, seizures, involuntary body movements, muscle atrophy, absent reflexes, and poor growth. He had multiple procedures for lacrimal duct stenosis and strabismus and had intractable blepharitis. He had severe osteopenia and persistent hypocholesterolemia. Whole exome sequencing revealed two novel variants in NGLY1: a truncating mutation, c.347C > G (p.S116X), and a splicing mutation, c.881 + 5G (p.IVS5 + 5G>T), predicted to abolish the splice donor site of exon 5. This study, along with previously reported cases, suggests that mutations in NGLY1 cause a recognizable phenotype and targeted sequencing should be considered in patients with typical presentation. This study expands the molecular spectrum of NGLY1-related condition and suggests that osteopenia and hypocholesterolemia may be part of the phenotype.

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Section: Discussionsupporting

confidence: 46%

Section: Discussionmentioning

confidence: 89%

Multi‐systemic involvement in NGLY1‐related disorder caused by two novel mutations

Heeley

Shinawi

2015

American J of Med Genetics Pt A

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“…It is also noteworthy that, when we examined the symptoms of NGLY1 -deficiency patients, there were a wide spectrum of symptoms and a genotype-phenotype correlation was not so obvious [23–25]. These results imply that the genetic background may influence the severity of the phenotypes caused by the defects of Ngly1 .…”

Section: Resultsmentioning

confidence: 99%

Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene

et al. 2017

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The cytoplasmic peptide:N-glycanase (Ngly1 in mammals) is a de-N-glycosylating enzyme that is highly conserved among eukaryotes. It was recently reported that subjects harboring mutations in the NGLY1 gene exhibited severe systemic symptoms (NGLY1-deficiency). While the enzyme obviously has a critical role in mammals, its precise function remains unclear. In this study, we analyzed Ngly1-deficient mice and found that they are embryonic lethal in C57BL/6 background. Surprisingly, the additional deletion of the gene encoding endo-β-N-acetylglucosaminidase (Engase), which is another de-N-glycosylating enzyme but leaves a single GlcNAc at glycosylated Asn residues, resulted in the partial rescue of the lethality of the Ngly1-deficient mice. Additionally, we also found that a change in the genetic background of C57BL/6 mice, produced by crossing the mice with an outbred mouse strain (ICR) could partially rescue the embryonic lethality of Ngly1-deficient mice. Viable Ngly1-deficient mice in a C57BL/6 and ICR mixed background, however, showed a very severe phenotype reminiscent of the symptoms of NGLY1-deficiency subjects. Again, many of those defects were strongly suppressed by the additional deletion of Engase in the C57BL/6 and ICR mixed background. The defects observed in Ngly1/Engase-deficient mice (C57BL/6 background) and Ngly1-deficient mice (C57BL/6 and ICR mixed background) closely resembled some of the symptoms of patients with an NGLY1-deficiency. These observations strongly suggest that the Ngly1- or Ngly1/Engase-deficient mice could serve as a valuable animal model for studies related to the pathogenesis of the NGLY1-deficiency, and that cytoplasmic ENGase represents one of the potential therapeutic targets for this genetic disorder.

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“…8,28,30,31 The phenotype of patient 2 with NGLY1 variants is similar to the previously reported patients, including the microcephaly, hypotonia, movement disorder, and alacrima. 28,32,33 Variants in SLC35A2 lead to CDG type 2m, featured by ID, epilepsy, facial dysmorphisms, and transient abnormalities in transferin testing. [34][35][36] In the seven reported patients with CDG type 2m, CVI has not been mentioned, but other features, including the facial dysmorphism, epilepsy and severe ID were present in patient 6.…”

Section: Resultsmentioning

confidence: 99%

Novel genetic causes for cerebral visual impairment

et al. 2015

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NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy

Cited by 72 publications

References 15 publications

Multi‐systemic involvement in NGLY1‐related disorder caused by two novel mutations

Multi‐systemic involvement in NGLY1‐related disorder caused by two novel mutations

Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene

Novel genetic causes for cerebral visual impairment

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