Anne Blomhoff

A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase ( PTPN22 ) confers susceptibility to generalised vitiligo

Vitiligo is an acquired hypomelanotic skin disorder resulting from the loss of functional melanocytes from the cutaneous epidermis and autoimmunity has been suggested to play a part in its pathogenesis. Recently, the missense R620W polymorphism in the PTPN22 gene, which encodes lymphoid protein tyrosine phosphatase (LYP), has been associated with susceptibility to autoimmune disorders. The objective of this study was to ascertain if the disease-associated 1858T allele was also associated with generalised (nonsegmental) vitiligo and so the frequencies of the PTPN22 1858C/T alleles were investigated in 165 English patients with generalised vitiligo and 304 ethnically matched control subjects. The results indicated that the 1858T allele was significantly over-represented in the vitiligo patient group compared with the control cohort. Of 330 vitiligo alleles, 48 (14.5%) encoded the Trp620 variant compared to 52 of 608 (8.6%) control alleles (P=0.006; odds ratio=1.82, 95% confidence interval=1.17–2.82). The results indicate that the LYP missense R620W polymorphism may have an influence on the development of generalised vitiligo and provide further evidence for autoimmunity as an aetiological factor with respect to this disease.

Mutation screening of PTPN22 : association of the 1858T-allele with Addison's disease

The tyrosine-protein phosphatase non-receptor type 22 (PTPN22) gene was recently identified as an important genetic susceptibility factor in several autoimmune diseases. The increased risk has been broadly explained by the 1858T-allele (rs2476601). As two smaller studies on Addisons disease (AD) have shown diverging results, we aimed to elucidate the predisposing effect of the single-nucleotide polymorphism (SNP) 1858CT in a larger population of AD patients, especially focusing on the AD patients with known autoimmune etiology. We also screened for unknown rare or common variants in the PTPN22 gene that could predispose for AD. The case–control study of Norwegian AD patients (n=332) and controls (n=990) showed a significant association between autoimmune AD (n=302) and the PTPN22 1858T risk allele (P=0.016). The association of AD with 1858T was supported by a meta-analysis combining our genotype data with that of others published previously (P=0.003). The mutation screening of PTPN22 in AD patients (n=332) and controls (n=112) revealed eight missense variants, five of which have not been reported previously. In conclusion, the 1858T-allele is a PTPN22 genetic susceptibility factor for autoimmune AD. Other rare variants in PTPN22 do occur, and may also be involved in the pathogenesis.

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.

Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB1 * 03 and DRB1 * 04 haplotypes

First generation linkage disequilibrium (LD) and haplotype maps of the human major histocompatibility complex (MHC) have been generated in order to aid the unraveling of the numerous disease predisposing genes in this region by offering a first set of haplotype tagSNPs. Several parameters, like the population studied, the marker map used, the density of polymorphisms and the applied algorithm, are influencing the appearance of haplotype blocks and selection of tags. The MHC comprises a limited number of ancestral, conserved haplotypes. We address the impact of the underlying HLA haplotypes on the LD patterns, haplotype blocks and tag selection throughout the entire extended MHC (xMHC) by studying DR-DQ haplotypes, mainly those carrying DRB1*03 and DRB1*04 alleles. We observed significantly different degree and extent of LD calculated on different HLA backgrounds, as well as variation in the size and boundaries of the defined haplotype and tags selected. Our results demonstrate that the underlying ancestral HLA haplotypic architecture is yet another parameter to take into consideration when constructing LD maps of the xMHC. This may be essential for mapping of disease susceptibility genes since many diseases are associated with and map on particular HLA haplotypes.

Haploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability.

BackgroundNineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1–17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes.Methods and resultsWe describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1–3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1–4 (189 kb) included the genes JARID2 and DTNBP1, while SRO II in Patients 1–3 and 5 (116 kb) contained GMPR and ATXN1. Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of JARID2. Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of ATXN1. Patients 1–3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both ATXN1 and JARID2. The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes.ConclusionsPatients carrying JARID2 deletion manifested with cognitive impairment, gait disturbance and a characteristic facial appearance, whereas patients with deletion of ATXN1 seemed to be characterized by intellectual disability and behavioural abnormalities. Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.

Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2

Biallelic mutations in IGHMBP2 cause spinal muscular atrophy with respiratory distress type 1 (SMARD1) or Charcot-Marie-Tooth type 2S (CMT2S). We report three families variably affected by IGHMBP2 mutations. Patient 1, an 8-year-old boy with two homozygous variants: c.2T>C and c.861C>G, was wheelchair bound due to sensorimotor axonal neuropathy and chronic respiratory failure. Patient 2 and his younger sister, Patient 3, had compound heterozygous variants: c.983_987delAAGAA and c.1478C>T. However, clinical phenotypes differed markedly as the elder with sensorimotor axonal neuropathy had still unaffected respiratory function at 4.5 years, whereas the younger presented as infantile spinal muscular atrophy and died from relentless respiratory failure at 11 months. Patient 4, a 6-year-old girl homozygous for IGHMBP2 c.449+1G>T documented to result in two aberrant transcripts, was wheelchair dependent due to axonal polyneuropathy. The clinical presentation in Patients 1 and 3 were consistent with SMARD1, whereas Patients 2 and 4 were in agreement with CMT2S.

Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B.

A pair of sisters was ascertained for multiple congenital defects, including marked craniofacial dysmorphisms with blepharophimosis, and severe psychomotor delay. Two novel compound heterozygous mutations in UBE3B were identified in both the sisters by exome sequencing. These mutations include c.1A>G, which predicts p.Met1?, and a c.1773delC variant, predicted to cause a frameshift at p.Phe591fs. UBE3B encodes a widely expressed protein ubiquitin ligase E3B, which, when mutated in both alleles, causes Kaufman oculocerebrofacial syndrome. We report on the thorough clinical examination of the patients and review the state of art knowledge of this disorder.

Homozygous KIDINS220 loss-of-function variants in fetuses with cerebral ventriculomegaly and limb contractures

Heterozygous mutations in KIDINS220 were recently suggested a cause of spastic paraplegia, intellectual disability, nystagmus and obesity. All patients carried terminal nonsense de novo mutations that seemed to escape nonsense-mediated mRNA decay. The mechanism for pathogenicity is yet unexplained, as it seems that heterozygous loss-of-function variants of KIDINS220 are generally well tolerated. We present a consanguineous couple who experienced four pregnancy terminations due to repeated findings in the fetuses comprising enlarged cerebral ventricles and limb contractures. Exome sequencing in two of the aborted fetuses revealed a shared homozygous frameshift variant in exon 24 in KIDINS220. Sanger sequencing of the variant in available family members showed complete segregation with the affection status, resulting in a LOD score of 2.5 under an autozygous inheritance model. mRNA studies revealed destruction of the original splice site, resulting in an out-of-frame transcript and introduction of a premature termination codon in exon 25. Premature termination codons in this position are likely to cause activation of nonsense-mediated mRNA decay and result in complete absence of KIDINS220 protein in individuals homozygous for the variant. The phenotype of the presented fetuses overlaps with findings in functional studies of knockout Kidins220 mice embryos that are non-viable with enlarged cerebral ventricles. The human fetuses also exhibit several similarities to the milder phenotype described in patients with heterozygous KIDINS220 mutations. We hence propose that the identified homozygous loss-of-function variant in KIDINS220 causes the phenotype in the presented fetuses, and that this represents a hitherto undescribed severe autosomal recessive neurodevelopmental disorder.