De Novo Mutation of Paternal IGF2 Gene Causing Silver–Russell Syndrome in a Sporadic Patient

Liu, Deguo; Wang, Yajian; Yang, Xiu‐An; Liu, Deyun

doi:10.3389/fgene.2017.00105

Cited by 36 publications

(29 citation statements)

References 20 publications

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“…Additionally, no exons indel was found by checking the NGS data. We recently encountered a patient with genetic disorder caused by imprinting gene 9 , therefore, we focused on the variants of imprinted genes. Finally, we locked into a genetic variant in MAGEL2 .…”

Section: Resultsmentioning

confidence: 99%

Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea

Tong

Wang²,

Lü

et al. 2018

Sci Rep

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Neurodevelopmental delay accompanied unexplained dyspnea is a highly lethal disease in clinic. This study is to investigate the performance characteristics of trio whole exome sequencing (Trio-WES) in a pediatric setting by presenting our patient cohort and displaying the diagnostic yield. A total of 31 pediatric patients showing neurodevelopmental delay accompanied unexplained dyspnea were admitted to our hospital and referred for molecular genetic testing using Trio-WES. Eight genes namely MMACHC, G6PC, G6PT, ETFDH, OTC, NDUFAF5, SLC22A5, and MAGEL2 were suspected to be responsible for the onset of the clinical symptoms and 6 variants were novel. Standard interpretation according to ACMG guideline showed that the variants were pathogenic. Finally, diagnosis of methylmalonic aciduria and homocystinuria, glycogen storage disease, ornithine transcarbamylase deficiency, glutaric acidemia II, mitochondrial complex 1 deficiency, carnitine deficiency, and Schaaf-Yang syndrome was made in 12 out of the 31 patients. Trio-WES is an effective means for molecular diagnosis of infantile neurodevelopmental delay accompanied unexplained dyspnea. As for molecular etiology identification, when routine potential monogenetic inheritance patterns including de novo, autosomal recessive, autosomal dominant, and X-linked recessive inheritance analysis is negative, physicians should take into account imprinted genes.

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Section: Resultsmentioning

confidence: 99%

Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea

Tong

Wang²,

Lü

et al. 2018

Sci Rep

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“…3F). Next, we investigated the capacity of the p.I66S variant to activate IGF1R, whereby an empty vector and the Schematic illustration of so far identified IGF2 mutations (9,11,12). IGF2 encode an inactive 180-aa (Isoform 1, NP_000603) or 236-aa (Isoform 2, NP_001121070) precursor protein that includes a 24-aa signal peptide (SP), a 67-aa core IGF2 and a 89-aa trailer sequence (18).…”

Section: The Igf2 Mutant Prevents Igf1r Activation Probably Through Amentioning

confidence: 99%

“…Begemann et al reported the first heterozygous IGF2 variation (NM_001127598: c.191C→A, p.Ser64Ter) in a multigenerational family with a severe growth retardation (9). Habib ), which might influence IGF2/IGF1R interaction (10,12). All mutations are located on the paternal allele.…”

Section: Introductionmentioning

confidence: 99%

A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation

Rockstroh

Pfäffle

Duc

et al. 2019

European Journal of Endocrinology

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Objective: The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation. Results: Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre-and postnatal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. Conclusion: The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders. Figure 3Illustration of potential conformational changes in p.I66S protein structure. (A) Schematic diagram of IGF2 maturation. IGF2 encodes an inactive 180-aa precursor protein which is post-translationally cleaved into a 67-aa bioactive protein. First, the terminal signal peptide is proteolytically removed creating a 156-aa sequence. In the next step, the trailer sequence is proteolytically cleaved at two separated sites (TQRLRR 104 and PAKSER 68 ) generating the bioactive protein. (B) Illustration of p.I66S protein structure. Sequence analyses of the cleavage sites indicated a changed aa sequence at basic residues in the mutant: TQRLRR→PSACAG and PAKSER→PPSPRG. (C) Comparison of the WT (IGF2-WT, blue) and mutant (IGF2-I66S, red) protein structure.3D protein structure was predicted based on the crystal structure of IGF2-WT (pdb: 1IGL) using the iTASSER server and superpositioned with the WT structure. The mostly unstructured C-terminal extension due to the lack of posttranslational processing is illustrated. (D) Upper panel: Schematic presentation of IGF2 plasmids. The position of the c.195delC mutation is marked in red. Lower panel: Cell lysates and supernatants from transfected cells after immunoblotting with the indicated antibodies. (E) Whole-cell lysates from IGF1 stimulated (30 min) cells transfected with an IGF1R plasmid were subjected to immunoblotting using antibodies as indicated. (F) Whole-cell lysates were prepared from IGF1R transfected cells after stimulation (30 min) with IGF2-WT supernatants and immunoblotted for pIGF1R, total IGF1R and β-actin as loading control. Representative blot out of three independent experiments is shown.Figure 4...

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“…Through exome analysis, the authors identified an IGF2 nonsense mutation in all patients, inherited from their healthy fathers (OMIM 616489) (51). After this first report, other five studies identified variants in IGF2 gene on the paternal allele causing SRS-like (52)(53)(54)(55)(56). Up to now, one missense and six loss-of-function variants (3 frameshift, 2 nonsense and 1 splice-site) in the IGF2 gene were reported.…”

Section: Igf2 Defectsmentioning

confidence: 98%

“…Five probands presented cardiac abnormalities, including patent ductus arteriosus and atrial or ventricular septal defects. Male genital abnormalities, as hypospadia, penoscrotal transposition, cryptorchidism and ambiguous genitalia were also reported (51)(52)(53)56).…”

Section: Igf2 Defectsmentioning

confidence: 99%

Update on new GH-IGF axis genetic defects

Vasques¹,

Andrade²,

Correa³

et al. 2019

Archives of Endocrinology and Metabolism

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The somatotropic axis is the main hormonal regulator of growth. Growth hormone (GH), also known as somatotropin, and insulin-like growth factor 1 (IGF-1) are the key components of the somatotropic axis. This axis has been studied for a long time and the knowledge of how some molecules could promote or impair hormones production and action has been growing over the last decade. The enhancement of large-scale sequencing techniques has expanded the spectrum of known genes and several other candidate genes that could affect the GH-IGF1-bone pathway. To date, defects in more than forty genes were associated with an impairment of the somatotropic axis. These defects can affect from the secretion of GH to the bioavailability and action of IGF-1. Affected patients present a large heterogeneous group of conditions associated with growth retardation. In this review, we focus on the description of the GH-IGF axis genetic defects reported in the last decade.

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De Novo Mutation of Paternal IGF2 Gene Causing Silver–Russell Syndrome in a Sporadic Patient

Cited by 36 publications

References 20 publications

Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea

Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea

A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation

Update on new GH-IGF axis genetic defects

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