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Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1.

ABSTRACT: Loss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID).Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-γ/IL-17(+) T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer.Patient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2 months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4 months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154C > T; p.T385M; P2. c.971G > T; p.C324F). Circulating CD4(+) T cells of both patients exhibited increased interferon-γ and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-β and -γ-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib.STAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.

SUBMITTER: Baris S

PROVIDER: S-EPMC5556363 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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Project description:To identify genetic mutations in three families with early onset high myopia (eoHM) limited to female members.Genomic DNA was collected from participating members of families XF1, XF2, and XF3. Genome-wide linkage scans were performed on the largest family (XF1). Whole exome sequencing was performed on seven samples, including five samples (four affected and one unaffected) from family XF1, as well as the two probands from family XF2 and XF3. Variants were analyzed with multistep bioinformatics analyses. Sanger-dideoxy sequencing was used to verify candidate variations in families and controls.The genome-wide linkage scans performed on family XF1 detected a candidate locus on chromosome Xp11.1-Xq13.3 with a maximum logarithm of the odds (LOD) score of 2.48 and 3.01 for markers DXS991 and DXS986, respectively. Parallel whole exome sequencing identified a novel c.893C>A (p.Ala298Asp) mutation in ARR3 located on Xq13.1 in family XF1, which was shared by all four affected individuals but not the unaffected individual. Two other novel mutations in ARR3, c.298C>T (p.Arg100*) and c.239T>C (p.Leu80Pro), were detected in families XF2 and XF3, respectively. These mutations were predicted to be damaging and were not present in the normal controls and existing databases. All three mutations cosegregated with eoHM in each of the three families, in which all heterozygous female members are affected whereas all hemizygous male family members are not affected. Transmission of the mutations and eoHM in the three families demonstrates an unusual pattern of X-linked female-limited inheritance.These data suggest that heterozygous mutations in ARR3 might be responsible for X-linked female-limited eoHM in the three families, a pattern contrary to the standard X-linked recessive trait. To our knowledge, eoHM is the first human disease associated with mutations in ARR3 and the second X-linked female-limited disease identified thus far. Identification of ARR3 associated with X-linked female-limited trait provides not only additional evidence of this unusual hereditary pattern but also an additional model for investigating the molecular mechanism responsible for female-limited phenotypes.

Project description:BackgroundEpileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease.Case presentationWe sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease.ConclusionsWe describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease.

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Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1.

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