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  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
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Alternative titles; symbolsRAS-LIKE GTPase GENE; RLGPHGNC Approved Gene Symbol: RAB40ALCytogenetic location: Xq22.1 Genomic coordinates (GRCh38): X:102,937,2...

Alternative titles; symbols


HGNC Approved Gene Symbol: RAB40AL

Cytogenetic location: Xq22.1 Genomic coordinates (GRCh38): X:102,937,271-102,938,299 (from NCBI)

▼ Cloning and Expression
Saito-Ohara et al. (2002) identified the RAB40AL gene, which showed a high degree of homology to the yeast Sec4 gene, and encoded a putative small guanine protein that the authors termed RLGP for Ras-like GTPase. Immunocytochemistry located RAB40AL to the mitochondria.

Bedoyan et al. (2012) found that RAB40AL was expressed in human brain and kidney. Expression in fetal lung, heart, liver, and skeletal muscle appeared lower than in adult tissues.

▼ Mapping
Saito-Ohara et al. (2002) identified the RAB40AL gene at the Xq22.2 breakpoint of a pericentric inversion of the X chromosome.

▼ Evolution
Bedoyan et al. (2012) identified RAB40AL orthologs in primates such as rhesus monkeys and chimpanzees, but not in dog, rat, mouse, Xenopus, or zebrafish. Nucleotide and protein analyses indicated that mouse Rab40b showed the highest identity (83%) and similarity (91%) to human RAB40AL; however, the ortholog of Rab40b on mouse chromosome 11 is RAB40B (619550) on human chromosome 17. Human RAB40A (301065) shows 99% protein identity and similarity to RAB40AL. RAB40A is about 560-kb telomeric to RAB40AL on the X chromosome and is flanked by repetitive sequences. The apparent restriction of RAB40AL to primates suggested a recent evolutionary divergence and was consistent with a hypothesized functional role of RAB40AL in neurodevelopment.

▼ Cytogenetics
Saito-Ohara et al. (2002) studied a 16-year-old patient with Duchenne muscular dystrophy (310200), profound mental retardation, athetosis, and nystagmus who was shown to have a pericentric inversion of the X chromosome, 46,Y,inv(X)(p21.2q22.2). His mother carried this inversion on one allele. The patient's condition was originally misdiagnosed as cerebral palsy. Because the DMD gene (dystrophin; 300377) is located at Xp21.2, which is one breakpoint of the inv(X), and because its defects are rarely associated with severe mental retardation, the other clinical features of this patient were deemed likely to be associated with the opposite breakpoint at Xq22. The molecular-cytogenetic characterization of both breakpoints revealed 3 genetic events that probably had disastrous influence on neuromuscular and cognitive development: deletion of part of the DMD gene at Xp21.2, duplication of the proteolipid protein gene (PLP1; 300401) at Xq22.2, and disruption of the RAB40AL gene. Saito-Ohara et al. (2002) speculated that disruption of RAB40AL was responsible for the patient's profound mental retardation.

▼ Molecular Genetics
For discussion of a possible association between Martin-Probst syndrome (MRXSMP; 300519) and variation in the RAB40AL gene, see 300405.0001.

▼ ALLELIC VARIANTS ( 1 Selected Example):

This variant, formerly titled MARTIN-PROBST SYNDROME, has been reclassified based on the findings of Oldak et al. (2014).

In 2 affected males of a family with Martin-Probst syndrome (MRXSMP; 300519), Bedoyan et al. (2012) identified an AC-GA change in the RAB40AL gene, resulting in an asp59-to-gly (D59G) substitution at a highly conserved residue in a loop region between 2 presumptive beta-strands within the GTPase domain. The variant was identified by massively parallel sequencing. Transfection of the variant protein in COS-7 cells resulted in decreased protein detection compared to wildtype, suggesting instability and degradation of the protein. The variant protein showed abnormal localization, with accumulation in the nucleus or perinuclear region, rather than the cytoplasm. All obligate and nonobligate female family members with skewed X inactivation were heterozygous for the variant, which was not found in 297 controls or in the 1000 Genomes Project or Exome Sequencing Project databases.

Lee et al. (2014) identified a hemizygous D59G variant in a 20-year-old male with profound mental retardation, central hypotonia, peripheral spastic quadriplegia, seizures, optic atrophy, and hearing loss. Other features included dysautonomia with temperature instability, short stature, and undescended testes. Dysmorphic features were mild, and included a broad nasal root, malar hypoplasia, and a full lower lip. Lee et al. (2014) concluded that the phenotype in their patient was consistent with an extremely severe form of MRXSMP.

Oldak et al. (2014) identified a hemizygous D59G variant in 2 unrelated males who did not have MRXSMP. The variants were found during whole-exome sequencing of these patients for unrelated phenotypes and did not segregate with the phenotypes in either family. Subsequent population studies identified the D59G variant in 8 of 405 Polish male controls and in 12 of 405 Polish female controls, yielding a frequency of 2.47%. Oldak et al. (2014) concluded that the D59G variant is a polymorphism that is not responsible for MRXSMP.

Oldak et al. (2014) stated that the c.176_177delACinsGA variant, predicted to cause a replacement of aspartic acid by glycine (GAC-GGA) at codon 59 (D59G), can also be described as a c.176A-G transition (rs145606134) cooccurring with a c.177C-A transversion (rs138133927).

Tags: Xq22.1