Hypomyelinating leukodystrophies are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. We used whole exome analysis to study the molecular basis of hypomyelinating leukodystrophy in two sibs from a consanguineous family. A homozygous mutation, c.3068+5G>A, was identified in the ATRN gene, with the consequent insertion of an intronic sequence into the patients’ cDNA and a predicted premature termination of the ATRN polypeptide. ATRN encodes Attractin, which was previously shown to play a critical role in central myelination. Several spontaneous ATRN rodent mutants exhibited impaired myelination which was attributed to oxidative stress and accelerated apoptosis. ATRN can now be added to the growing list of genes associated with hypomyelinating leukodystrophy. The disease seems to be confined to the CNS; however, given the young age of our patients, longer follow-up may be required. Keywords
Attractin Hypomyelination Leukodystrophy
Lisätietoa tästä geenistä PubMed Gene lähteestä:
Lisätietoa tästä geenistä PubMed Gene lähteestä:
- Also known as MGCA; DPPT-L
- Summary This gene encodes both membrane-bound and secreted protein isoforms. A membrane-bound isoform exhibits sequence similarity with the mouse mahogany protein, a receptor involved in controlling obesity. A secreted isoform is involved in the initial immune cell clustering during inflammatory responses that may regulate the chemotactic activity of chemokines. [provided by RefSeq, Apr 2016]
- Expression Ubiquitous expression in duodenum (RPKM 20.8), thyroid (RPKM 17.2) and 25 other tissues
- (Kelch-domeenit voi laskea jaksoista ,joissa on GG----Y----W motiivi.
NM_001207047.3 → NP_001193976.1 attractin isoform 4
- Transcript Variant: This variant (4) uses an alternate splice junction at the 3' end of the first exon and differs in the 3' UTR and coding region compared to variant 1. The resulting isoform (4) has distinct N- and C-termini compared to isoform 1. Unlike isoform 1, which is membrane-bound, isoform 4 is secreted.
- Source sequence(s)
- AK293010, AK302730, AL132773, BC101705, DA368237
- Conserved Domains (7) summary
Location:672 → 804
- (ALP)CLECT_attractin_like: C-type lectin-like domain (CTLD) of the type found in human and mouse attractin (AtrN) and attractin-like protein (ALP). CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. Mouse AtrN (the product of the mahogany gene) has been shown to bind Agouti protein and to function in agouti-induced pigmentation and obesity. Mutations in AtrN have also been shown to cause spongiform encephalopathy and hypomyelination in rats and hamsters. The cytoplasmic region of mouse ALP has been shown to binds to melanocortin receptor (MCR4). Signaling through MCR4 plays a role in appetite suppression. Attractin may have therapeutic potential in the treatment of obesity. Human attractin (hAtrN) has been shown to be expressed on activated T cells and released extracellularly. The circulating serum attractin induces the spreading of monocytes that become the focus of the clustering of non-proliferating T cells.
Location:23 → 131
- CUB; CUB domain; extracellular domain; present in proteins mostly known to be involved in development; not found in prokaryotes, plants and yeast.
Location:946 → 991
- EGF_Lam; Laminin-type epidermal growth factor-like domain; laminins are the major noncollagenous components of basement membranes that mediate cell adhesion, growth migration, and differentiation; the laminin-type epidermal growth factor-like module occurs in ...
Location:385 → 434
- Kelch; KELCH repeat [structural motif]
Location:816 → 867
- PSI; Plexin repeat
Location:234 → 284
- Kelch_3; Galactose oxidase, central domain
Location:274 → 312
- Kelch_5; Kelch motif
REFERENCE 3 (residues 1 to 1156) AUTHORS Laudes M, Oberhauser F, Schulte DM, Schilbach K, Freude S, Bilkovski R, Schulz O, Faust M and Krone W. TITLE Dipeptidyl-peptidase 4 and attractin expression is increased in circulating blood monocytes of obese human subjects JOURNAL Exp. Clin. Endocrinol. Diabetes 118 (8), 473-477 (2010) PUBMED 20198559 REMARK GeneRIF: The levels of both dipeptidyl-peptidase 4 and attractin in circulating monocytes were significantly higher in obese subjects as compared with levels in lean controls or in subjects with type 2 diabetes.Atraktiinivajeen merkitys. Tutkimuskoe-eläimeltä:)
- Brain Res. 2010 Feb 2;1312:145-55. doi: 10.1016/j.brainres.2009.11.027. Epub 2009 Nov 18.Abnormal myelinogenesis both in the white and gray matter of the attractin-deficient mv rat.
- Laboratory of Veterinary Pathology, Osaka Prefecture University, Rinku Orai-Kita, Izumisano, Osaka 598-8531, Japan.
AbstractThe myelin vacuolation (mv) rat exhibits hypomyelination and vacuole formation in the myelin throughout the CNS, caused by a null mutation in the attractin gene. Myelin alterations in the spinal cord of mv rats progress during postnatal development and are more prominent in the white matter. In contrast, microglial activation is confined to the gray matter of mv rats. We here investigate the distribution and expression patterns of major CNS myelin proteins in the spinal cord of mv rats during the development of the myelin lesions. Immunohistochemical and Western blot analyses demonstrated a considerable reduction in the expression of major CNS myelin proteins both in the white and gray matter of mv rats, which was consistent with the morphological alterations of myelin sheaths. Real-time PCR analysis revealed a significant decrease in expression of proteolipid protein (PLP) mRNA both in the white and gray matter of mv rats. However, there was no significant difference between control and mv rats in the cell number of PLP mRNA-positive oligodendrocytes either in the white or gray matter, suggesting an impairment of myelin protein production by oligodendrocytes. Our results indicate that myelinogenesis but not oligodendrogenesis is severely altered both in the white and gray matter of mv rats.
(c) 2009 Elsevier B.V. All rights reserved.