The alkylglycerol monooxygenase (AGMO) gene previously involved in autism also causes a novel syndromic form of primary microcephaly in a consanguineous Saudi family

Alrayes, Nuha; Mohamoud, Hussein Sheikh Ali; Ahmed, Saleem; Almramhi, Mona Mohammad; Shuaib, Taghreed; Wang, Jun; Al‐Aama, Jumana Y.; Everett, Kate V.; Nasir, Jamal; Jelani, Musharraf

doi:10.1016/j.jns.2016.02.063

Cited by 17 publications

(13 citation statements)

References 37 publications

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“…Queuine deficiency in human cells in vitro and in animals results in a reduced level of the cofactor tetrahydrobiopterin, BH4 (106). BH4 is a necessary cofactor for the conversion of phenylalanine to tyrosine, of tryptophan to serotonin, of tyrosine to DOPA (which gets converted into epinephrine and norepinephrine), of arginine to NO, and for the oxidation of alkyl glycerol lipids (107,108). The essentiality of BH4 for the hydroxylation of tryptophan to produce serotonin could be of relevance to numerous neurological conditions, especially considering serotonin's role as a social hormone controlling executive function, and its relevance to autism, attention deficit/hyperactivity disorder, bipolar, and schizophrenia (12,13,(109)(110)(111).…”

Section: Conditional Vitaminsmentioning

confidence: 99%

Prolonging healthy aging: Longevity vitamins and proteins

Ames¹

2018

Proc. Natl. Acad. Sci. U.S.A.

188

133

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It is proposed that proteins/enzymes be classified into two classes according to their essentiality for immediate survival/reproduction and their function in long-term health: that is, survival proteins versus longevity proteins. As proposed by the triage theory, a modest deficiency of one of the nutrients/cofactors triggers a built-in rationing mechanism that favors the proteins needed for immediate survival and reproduction (survival proteins) while sacrificing those needed to protect against future damage (longevity proteins). Impairment of the function of longevity proteins results in an insidious acceleration of the risk of diseases associated with aging. I also propose that nutrients required for the function of longevity proteins constitute a class of vitamins that are here named “longevity vitamins.” I suggest that many such nutrients play a dual role for both survival and longevity. The evidence for classifying taurine as a conditional vitamin, and the following 10 compounds as putative longevity vitamins, is reviewed: the fungal antioxidant ergothioneine; the bacterial metabolites pyrroloquinoline quinone (PQQ) and queuine; and the plant antioxidant carotenoids lutein, zeaxanthin, lycopene, α- and β-carotene, β-cryptoxanthin, and the marine carotenoid astaxanthin. Because nutrient deficiencies are highly prevalent in the United States (and elsewhere), appropriate supplementation and/or an improved diet could reduce much of the consequent risk of chronic disease and premature aging.

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Section: Conditional Vitaminsmentioning

confidence: 99%

Prolonging healthy aging: Longevity vitamins and proteins

Ames¹

2018

Proc. Natl. Acad. Sci. U.S.A.

188

133

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“…We next performed WES on one proband (V-1), using a commercial supplier ( Macrogen ). The data were filtered and sorted as previously reported 4 – 6 . We screened for novel stop-gain mutations, homozygous nonsynonymous SNPs and indels occurring at a frequency of less than 0.001, within the common regions of homozygosity identified by the array CGH array.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate the possible involvement of chromosomal aberrations, and for the purpose of homozygosity mapping, we performed microarray analysis ( Illumina , San Diego, CA, USA) on affected patients and their parents as previously described 5 , 6 . Whole exome paired-end sequencing, bioinformatic analyses and validation of the candidate genes by Sanger sequencing were also performed as previously described 5 , 6 .…”

Section: Methodsmentioning

confidence: 99%

“…We previously employed CGH arrays to identify regions of homozygosity and combined this with whole-exome sequencing (WES) to identify genes associated with complex neurological disorders 4 – 6 . Here, we report the identification of a large extended pedigree with intellectual disability (ID), facial dysmorphism, speech delay and developmental abnormalities, including postaxial polydactyly.…”

Section: Introductionmentioning

confidence: 99%

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A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features

Mohamoud

Ahmed

Jelani

et al. 2018

Sci Rep

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Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities.

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“… 23 – 25 Furthermore, recently identified syndromic microcephaly AGMO, RTTN and PGAP2 genes have been reported in the Saudi population. 26 – 28 …”

mentioning

confidence: 99%

A novel WDR62 mutation causes primary microcephaly in a large consanguineous Saudi family

Naseer

Rasool

Sogaty

et al. 2017

Annals of Saudi Medicine

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BACKGROUNDPrimary microcephaly (MCPH) is a rare developmental defect characterized by impaired cognitive functions, retarded neurodevelopment and reduced brain size. It is genetically heterogeneous and more than 17 genes so far have been identified that are associated with this disease.OBJECTIVETo study the genetic defect in a consanguineous Saudi family with primary microcephaly.DESIGNCross-sectional clinical genetics study of a Saudi family.SETTINGMedical genomics research center.PATIENTS AND METHODSBlood samples collected from six members of a family of healthy consanguineous parents were analyzed by whole exome sequencing to identify the underlying pathogenic mutations in two members of the family (23-year-old female and 7-year-old male) who presented with primary microcephaly, intellectual disability, delayed psychomotor development and walking difficulty, speech impediments and seizures.MAIN OUTCOME MEASURE(S)Detection of mutation in the WD repeat domain 62 (WDR62) gene in a family segregating autosomal recessive primary microcephaly.RESULTSThe exome variant analysis identified a novel missense mutation (c.3878C>A) in WDR62 gene in exon 30 resulting in amino acid change from alanine to aspartate (p.Ala1293Asp). Further validation in the affected patients and healthy members of family and 100 unrelated healthy persons as controls confirmed it to be pathogenic.CONCLUSIONSFunctional impairment of the WDR62 gene can lead to severe neurodevelopmental defects, brain malformations and reduced head size. A missense mutation of exon 30 changed alanine to aspartate in the WDR62 protein leading to the typical MCPH phenotype.LIMITATIONSMutation was identified in a single family.

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The alkylglycerol monooxygenase (AGMO) gene previously involved in autism also causes a novel syndromic form of primary microcephaly in a consanguineous Saudi family

Cited by 17 publications

References 37 publications

Prolonging healthy aging: Longevity vitamins and proteins

Prolonging healthy aging: Longevity vitamins and proteins

A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features

A novel WDR62 mutation causes primary microcephaly in a large consanguineous Saudi family

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