JAK3 mutations in Italian patients affected by SCID: New molecular aspects of a long-known gene

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Abstract

BACKGROUND: Mutations in the Janus Kinase 3 (JAK3) gene cause an autosomal recessive form of severe combined immunodeficiency (SCID) usually characterized by the absence of both T and NK cells, but preserved numbers of B lymphocytes (T-B+NK-SCID). The detection of larger (>100 bp) genomic duplications or deletions can be more difficult to be detected by PCR-based methods or standard NGS protocols, and a broad range of mutation detection techniques are necessary.

METHODS: We report four unrelated Italian patients (two females and two males) with SCID phenotype. Protein expression, functional studies, molecular analysis by standard methods and NGS, and transcripts studies were performed to obtain a definitive diagnosis.

RESULTS: Here, we describe four JAK3-deficient patients from four unrelated families. The first patient is homozygous for the known c.1951 C>T mutation causing the amino acidic change p.R651W. The other two patients, originating from the same small Italian town, resulted compound heterozygotes for the same g.15410_16542del deletion and two different novel mutations, g.13319_13321delTTC and c.933T>G (p.F292V), respectively. The fourth patient was compound heterozygous for the novel mutations p.V599G and p.W709R. Defective STAT5 phosphorylation after IL2 or IL15 stimulation corroborated the mutation pathogenicity. Concerning g.15410_16542del mutation, probably due to an unequal homologous recombination between Alu elements of JAK3 gene, microsatellites analysis revealed that both unrelated Pt2 and Pt3 and their carrier family members shared the same haplotype. These data support the hypothesis of a founder effect for the g.15410_16542del mutation that might have inherited in both unrelated families from the same ancient progenitor.

CONCLUSION: Different molecular techniques are still required to obtain a definitive diagnosis of AR-SCID particularly in all cases in which a monoallelic mutation is found by standard mutation scanning methods.

Original languageEnglish
Pages (from-to)713-721
Number of pages9
JournalMolecular genetics & genomic medicine
Volume6
Issue number5
DOIs
Publication statusPublished - Sep 2018

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Janus Kinase 3
Severe Combined Immunodeficiency
Mutation
Genes
Alu Elements
Founder Effect
Interleukin-15
Homologous Recombination
Heterozygote
Natural Killer Cells
Microsatellite Repeats
Haplotypes
Interleukin-2
Virulence

Cite this

@article{8555565722404c989f9482e72ce14f24,
title = "JAK3 mutations in Italian patients affected by SCID: New molecular aspects of a long-known gene",
abstract = "BACKGROUND: Mutations in the Janus Kinase 3 (JAK3) gene cause an autosomal recessive form of severe combined immunodeficiency (SCID) usually characterized by the absence of both T and NK cells, but preserved numbers of B lymphocytes (T-B+NK-SCID). The detection of larger (>100 bp) genomic duplications or deletions can be more difficult to be detected by PCR-based methods or standard NGS protocols, and a broad range of mutation detection techniques are necessary.METHODS: We report four unrelated Italian patients (two females and two males) with SCID phenotype. Protein expression, functional studies, molecular analysis by standard methods and NGS, and transcripts studies were performed to obtain a definitive diagnosis.RESULTS: Here, we describe four JAK3-deficient patients from four unrelated families. The first patient is homozygous for the known c.1951 C>T mutation causing the amino acidic change p.R651W. The other two patients, originating from the same small Italian town, resulted compound heterozygotes for the same g.15410_16542del deletion and two different novel mutations, g.13319_13321delTTC and c.933T>G (p.F292V), respectively. The fourth patient was compound heterozygous for the novel mutations p.V599G and p.W709R. Defective STAT5 phosphorylation after IL2 or IL15 stimulation corroborated the mutation pathogenicity. Concerning g.15410_16542del mutation, probably due to an unequal homologous recombination between Alu elements of JAK3 gene, microsatellites analysis revealed that both unrelated Pt2 and Pt3 and their carrier family members shared the same haplotype. These data support the hypothesis of a founder effect for the g.15410_16542del mutation that might have inherited in both unrelated families from the same ancient progenitor.CONCLUSION: Different molecular techniques are still required to obtain a definitive diagnosis of AR-SCID particularly in all cases in which a monoallelic mutation is found by standard mutation scanning methods.",
author = "{Di Matteo}, Gigliola and Maria Chiriaco and Alessia Scarselli and Cristina Cifaldi and Susanna Livadiotti and {Di Cesare}, Silvia and Valentina Ferradini and Alessandro Aiuti and Paolo Rossi and Andrea Finocchi and Caterina Cancrini",
note = "{\circledC} 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.",
year = "2018",
month = "9",
doi = "10.1002/mgg3.391",
language = "English",
volume = "6",
pages = "713--721",
journal = "Molecular genetics & genomic medicine",
issn = "2324-9269",
publisher = "John Wiley and Sons Inc.",
number = "5",

}

TY - JOUR

T1 - JAK3 mutations in Italian patients affected by SCID

T2 - New molecular aspects of a long-known gene

AU - Di Matteo, Gigliola

AU - Chiriaco, Maria

AU - Scarselli, Alessia

AU - Cifaldi, Cristina

AU - Livadiotti, Susanna

AU - Di Cesare, Silvia

AU - Ferradini, Valentina

AU - Aiuti, Alessandro

AU - Rossi, Paolo

AU - Finocchi, Andrea

AU - Cancrini, Caterina

N1 - © 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

PY - 2018/9

Y1 - 2018/9

N2 - BACKGROUND: Mutations in the Janus Kinase 3 (JAK3) gene cause an autosomal recessive form of severe combined immunodeficiency (SCID) usually characterized by the absence of both T and NK cells, but preserved numbers of B lymphocytes (T-B+NK-SCID). The detection of larger (>100 bp) genomic duplications or deletions can be more difficult to be detected by PCR-based methods or standard NGS protocols, and a broad range of mutation detection techniques are necessary.METHODS: We report four unrelated Italian patients (two females and two males) with SCID phenotype. Protein expression, functional studies, molecular analysis by standard methods and NGS, and transcripts studies were performed to obtain a definitive diagnosis.RESULTS: Here, we describe four JAK3-deficient patients from four unrelated families. The first patient is homozygous for the known c.1951 C>T mutation causing the amino acidic change p.R651W. The other two patients, originating from the same small Italian town, resulted compound heterozygotes for the same g.15410_16542del deletion and two different novel mutations, g.13319_13321delTTC and c.933T>G (p.F292V), respectively. The fourth patient was compound heterozygous for the novel mutations p.V599G and p.W709R. Defective STAT5 phosphorylation after IL2 or IL15 stimulation corroborated the mutation pathogenicity. Concerning g.15410_16542del mutation, probably due to an unequal homologous recombination between Alu elements of JAK3 gene, microsatellites analysis revealed that both unrelated Pt2 and Pt3 and their carrier family members shared the same haplotype. These data support the hypothesis of a founder effect for the g.15410_16542del mutation that might have inherited in both unrelated families from the same ancient progenitor.CONCLUSION: Different molecular techniques are still required to obtain a definitive diagnosis of AR-SCID particularly in all cases in which a monoallelic mutation is found by standard mutation scanning methods.

AB - BACKGROUND: Mutations in the Janus Kinase 3 (JAK3) gene cause an autosomal recessive form of severe combined immunodeficiency (SCID) usually characterized by the absence of both T and NK cells, but preserved numbers of B lymphocytes (T-B+NK-SCID). The detection of larger (>100 bp) genomic duplications or deletions can be more difficult to be detected by PCR-based methods or standard NGS protocols, and a broad range of mutation detection techniques are necessary.METHODS: We report four unrelated Italian patients (two females and two males) with SCID phenotype. Protein expression, functional studies, molecular analysis by standard methods and NGS, and transcripts studies were performed to obtain a definitive diagnosis.RESULTS: Here, we describe four JAK3-deficient patients from four unrelated families. The first patient is homozygous for the known c.1951 C>T mutation causing the amino acidic change p.R651W. The other two patients, originating from the same small Italian town, resulted compound heterozygotes for the same g.15410_16542del deletion and two different novel mutations, g.13319_13321delTTC and c.933T>G (p.F292V), respectively. The fourth patient was compound heterozygous for the novel mutations p.V599G and p.W709R. Defective STAT5 phosphorylation after IL2 or IL15 stimulation corroborated the mutation pathogenicity. Concerning g.15410_16542del mutation, probably due to an unequal homologous recombination between Alu elements of JAK3 gene, microsatellites analysis revealed that both unrelated Pt2 and Pt3 and their carrier family members shared the same haplotype. These data support the hypothesis of a founder effect for the g.15410_16542del mutation that might have inherited in both unrelated families from the same ancient progenitor.CONCLUSION: Different molecular techniques are still required to obtain a definitive diagnosis of AR-SCID particularly in all cases in which a monoallelic mutation is found by standard mutation scanning methods.

U2 - 10.1002/mgg3.391

DO - 10.1002/mgg3.391

M3 - Article

C2 - 30032486

VL - 6

SP - 713

EP - 721

JO - Molecular genetics & genomic medicine

JF - Molecular genetics & genomic medicine

SN - 2324-9269

IS - 5

ER -