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Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism.

Shaheen R, Abdel-Salam GM, Guy MP, Alomar R, Abdel-Hamid MS, Afifi HH, Ismail SI, Emam BA, Phizicky EM, Alkuraya FS - Genome Biol. (2015)

Bottom Line: Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant.WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m(7)G46) methylation of tRNA.The human mutation and the corresponding yeast mutation result in a significant reduction of m(7)G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m(7)G46 modification causes a growth deficiency phenotype in yeast.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

ABSTRACT

Background: Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity.

Results: Two presumably unrelated consanguineous families presented with an apparently novel form of primordial dwarfism in which severe growth deficiency is accompanied by distinct facial dysmorphism, brain malformation (microcephaly, agenesis of corpus callosum, and simplified gyration), and severe encephalopathy with seizures. Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant. WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m(7)G46) methylation of tRNA. The human mutation and the corresponding yeast mutation result in a significant reduction of m(7)G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m(7)G46 modification causes a growth deficiency phenotype in yeast.

Conclusion: Our study expands the number of biological pathways underlying primordial dwarfism and adds to a growing list of human diseases linked to abnormal tRNA modification.

No MeSH data available.


Related in: MedlinePlus

Identification of a novel PD syndrome. a Family pedigree of 14DG1157 & 14DG1160 showing the consanguineous nature of the parents. The index is indicated in each pedigree by an arrow, and asterisks denote individuals whose DNA was available for analysis. b, c Facial images for the index of each family showing the highly similar dysmorphic profile consisting of high forehead, prominent eyes, depressed nasal bridge, short philtrum, tented upper lip and bulged alveolar ridge, and prominent ear lobule. d–g MRI image of 14DG1160 showing partial agenesis of corpus callosum, and abnormal gyral pattern most pronounced posteriorly
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Fig1: Identification of a novel PD syndrome. a Family pedigree of 14DG1157 & 14DG1160 showing the consanguineous nature of the parents. The index is indicated in each pedigree by an arrow, and asterisks denote individuals whose DNA was available for analysis. b, c Facial images for the index of each family showing the highly similar dysmorphic profile consisting of high forehead, prominent eyes, depressed nasal bridge, short philtrum, tented upper lip and bulged alveolar ridge, and prominent ear lobule. d–g MRI image of 14DG1160 showing partial agenesis of corpus callosum, and abnormal gyral pattern most pronounced posteriorly

Mentions: This female infant was born to a 20-year-old mother and 26-year-old father by normal vaginal delivery at 37-weeks’ gestation. The parents are healthy first cousins (Fig. 1a). The family history is non-contributory. The couple had a subsequent boy who died a few days after birth because of growth retardation and multiple congenital heart anomalies. During the gestation of patient 1, the pregnancy was complicated by threatened abortion in the first trimester. Intrauterine growth retardation and weak fetal movements were also documented. The birth weight was 1,600 g. The birth length and head circumference were not recorded but mentioned to be small. She was referred to the Clinical Genetics Department at the age of 4 months because of poor gain of weight and for genetic counseling. On clinical examination she was noted to have a head circumference of 31.5 cm (−5 SD) weight of 2,800 g (−6 SD), and length of 48 cm (−5 SD). The patient had a high forehead, prominent eyes, depressed nasal bridge, short philtrum, tented upper lip and bulged alveolar ridge, and prominent ear lobule (Fig. 1b).Fig. 1


Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism.

Shaheen R, Abdel-Salam GM, Guy MP, Alomar R, Abdel-Hamid MS, Afifi HH, Ismail SI, Emam BA, Phizicky EM, Alkuraya FS - Genome Biol. (2015)

Identification of a novel PD syndrome. a Family pedigree of 14DG1157 & 14DG1160 showing the consanguineous nature of the parents. The index is indicated in each pedigree by an arrow, and asterisks denote individuals whose DNA was available for analysis. b, c Facial images for the index of each family showing the highly similar dysmorphic profile consisting of high forehead, prominent eyes, depressed nasal bridge, short philtrum, tented upper lip and bulged alveolar ridge, and prominent ear lobule. d–g MRI image of 14DG1160 showing partial agenesis of corpus callosum, and abnormal gyral pattern most pronounced posteriorly
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4587777&req=5

Fig1: Identification of a novel PD syndrome. a Family pedigree of 14DG1157 & 14DG1160 showing the consanguineous nature of the parents. The index is indicated in each pedigree by an arrow, and asterisks denote individuals whose DNA was available for analysis. b, c Facial images for the index of each family showing the highly similar dysmorphic profile consisting of high forehead, prominent eyes, depressed nasal bridge, short philtrum, tented upper lip and bulged alveolar ridge, and prominent ear lobule. d–g MRI image of 14DG1160 showing partial agenesis of corpus callosum, and abnormal gyral pattern most pronounced posteriorly
Mentions: This female infant was born to a 20-year-old mother and 26-year-old father by normal vaginal delivery at 37-weeks’ gestation. The parents are healthy first cousins (Fig. 1a). The family history is non-contributory. The couple had a subsequent boy who died a few days after birth because of growth retardation and multiple congenital heart anomalies. During the gestation of patient 1, the pregnancy was complicated by threatened abortion in the first trimester. Intrauterine growth retardation and weak fetal movements were also documented. The birth weight was 1,600 g. The birth length and head circumference were not recorded but mentioned to be small. She was referred to the Clinical Genetics Department at the age of 4 months because of poor gain of weight and for genetic counseling. On clinical examination she was noted to have a head circumference of 31.5 cm (−5 SD) weight of 2,800 g (−6 SD), and length of 48 cm (−5 SD). The patient had a high forehead, prominent eyes, depressed nasal bridge, short philtrum, tented upper lip and bulged alveolar ridge, and prominent ear lobule (Fig. 1b).Fig. 1

Bottom Line: Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant.WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m(7)G46) methylation of tRNA.The human mutation and the corresponding yeast mutation result in a significant reduction of m(7)G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m(7)G46 modification causes a growth deficiency phenotype in yeast.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

ABSTRACT

Background: Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity.

Results: Two presumably unrelated consanguineous families presented with an apparently novel form of primordial dwarfism in which severe growth deficiency is accompanied by distinct facial dysmorphism, brain malformation (microcephaly, agenesis of corpus callosum, and simplified gyration), and severe encephalopathy with seizures. Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant. WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m(7)G46) methylation of tRNA. The human mutation and the corresponding yeast mutation result in a significant reduction of m(7)G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m(7)G46 modification causes a growth deficiency phenotype in yeast.

Conclusion: Our study expands the number of biological pathways underlying primordial dwarfism and adds to a growing list of human diseases linked to abnormal tRNA modification.

No MeSH data available.


Related in: MedlinePlus