DENN Domain-Containing Protein 5A

Alternative Names

  • DENND5A
  • RAB6-Interacting Protein 1
  • RAB6IP1
  • KIAA1091
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OMIM Number

617278

NCBI Gene ID

23258

Uniprot ID

Q6IQ26

Length

126,526 bases

No. of Exons

24

No. of isoforms

2

Protein Name

DENN domain-containing protein 5A

Molecular Mass

147096 Da

Amino Acid Count

1287

Genomic Location

chr11:9,138,825-9,265,350

Gene Map Locus
11p15.4

Description

DENND5A encodes a protein that functions as a guanine nucleotide exchanger factor (GEF). These GEF proteins activate RAB GTPases by promoting the replacement of GDP by GTP in association with the GTPase. The DENND5A protein specifically functions as a guanine nucleotide exchange factor for the activation of RAB39. The protein is also a component of the trans-Golgi network; it is involved in calcium ion transmembrane transport and has been found to interact with RAB6 and SNX1 to regulate Golgi traffic.

The gene is associated with Epileptic Encephalopathy, Early Infantile, 49 (EIEE49), a severe autosomal recessive disorder characterized by neonatal-onset seizures, intellectual disability, global developmental delay, microcephaly, hypotonia, spasticity and facial dysmorphia.

Epidemiology in the Arab World

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Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_015213.4:c.2547delJordanNC_000011.10:g.9150740delPathogenicPathogenicDevelopmental and Epileptic Encephalopathy 49NG_053019.1:g.119597del; NM_015213.4:c.2547del; NP_056028.2:p.Lys850SerfsTer111057519308374926
NM_015213.4:c.517_518delSaudi ArabiaNC_000011.10:g.9204092CT[1]PathogenicPathogenicDevelopmental and Epileptic Encephalopathy 49NG_053019.1:g.66242GA[1]; NM_015213.4:c.517_518del; NP_056028.2:p.Asp173ProfsTer81057519307374925

Other Reports

Saudi Arabia

Anazi et al. (2016) studied 337 Intellectual Disability (ID) patients and found genomic tools to have a higher diagnostic yield than standard clinical evaluations. Exome sequencing helped identify DENND5A gene mutations in two patients: a homozygous loss-of-function mutation c.3811del (p.Gln1271Argfs*67) in a 26 month old female and a homozygous missense mutation c.1622A>G (p.Asp541Gly) in a 21 month old female. Both mutations had a minor allele frequency <0.001 based on 1500 Saudi exomes, fully segregated with the phenotype and there were no other candidate variants. The DENND5A gene was considered a candidate gene as it is a regulator of neurite outgrowth during neuronal differentiation. Further, the missense mutation was located in the dDENN domain and was predicted to affect the binding and functional efficiency between DENND5A and Rab GTPases. Both children were born to consanguineous parents and shared the phenotype of severe early infantile encephalopathy, progressive microcephaly, seizures, global developmental delay, central hypotonia and peripheral hypertonia. 

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