Objective
The pathologic basis of systemic juvenile idiopathic arthritis (JIA) is a subject of some controversy, with evidence for both autoimmune and autoinflammatory etiologies. Several monogenic ...autoinflammatory disorders have been described, but thus far, systemic JIA has only been attributed to a mutation of MEFV in rare cases and has been weakly associated with the HLA class II locus. This study was undertaken to identify the cause of an autosomal‐recessive form of systemic JIA.
Methods
We studied 13 patients with systemic JIA from 5 consanguineous families, all from the southern region of Saudi Arabia. We used linkage analysis, homozygosity mapping, and whole‐exome sequencing to identify the disease‐associated gene and mutation.
Results
Linkage analysis localized systemic JIA to a region on chromosome 13 with a maximum logarithm of odds score of 11.33, representing the strongest linkage identified to date for this disorder. Homozygosity mapping reduced the critical interval to a 1.02‐Mb region defined proximally by rs9533338 and distally by rs9595049. Whole‐exome sequencing identified a homoallelic missense mutation in LACC1, which encodes the enzyme laccase (multicopper oxidoreductase) domain–containing 1. The mutation was confirmed by Sanger sequencing and segregated with disease in all 5 families based on an autosomal‐recessive pattern of inheritance and complete penetrance.
Conclusion
Our findings provide strong genetic evidence of an association of a mutation in LACC1 with systemic JIA in the families studied. Association of LACC1 with Crohn's disease and leprosy has been reported and justifies investigation of its role in autoinflammatory disorders.
Molecular genetics studies are of increasing importance in the diagnosis and classification of congenital diarrheal disorders. We describe the molecular genetic basis of tricho-hepato-enteric ...syndrome in patients from Saudi Arabia with novel mutations of SKIV2L (c.3559_3579del, p.1187_1193del) and TTC37 (C4102T, p.Q1368X). Interestingly, the congenital presence of café-au-lait spots and their distribution in the pelvis and lower limbs were a unique and consistent clinical feature of these patients and may aid differential diagnosis of congenital diarrheal disorders. This study expands allelic and phenotypic heterogeneity of syndromic diarrhea/tricho-hepato-enteric syndrome.
Our study describes a novel phenotype in a series of nine Saudi patients with lactic acidosis, from four consanguineous families three of which are related. Detailed genetic studies including ...linkage, homozygosity mapping and targeted sequencing identified a causative mutation in the
BCS1L
gene. All affected members of the families have an identical mutation in this gene, mutations of which are recognized causes of Björnstad syndrome, GRACILE syndrome and a syndrome of neonatal tubulopathy, encephalopathy, and liver failure (MIM 606104) leading to isolated mitochondrial respiratory chain complex III deficiency. Here we report the appearance of a novel behavioral (five patients) and psychiatric (two patients) phenotype associated with a p.Gly129Arg
BCS1L
mutation, differing from the phenotype in a previously reported singleton patient with this mutation. The psychiatric symptoms emanated after childhood, initially as hypomania later evolving into intermittent psychosis. Neuroradiological findings included subtle white matter abnormalities, whilst muscle histopathology and respiratory chain studies confirmed respiratory chain dysfunction. The variable neuro-psychiatric manifestations and cortical visual dysfunction are most unusual and not reported associated with other
BCS1L
mutations. This report emphasizes the clinical heterogeneity associated with the mutation in
BCS1L
gene, even within the same family and we recommend that defects in this gene should be considered in the differential diagnosis of lactic acidosis with variable involvement of different organs.
Abstract Farber disease is a rare inherited lysosomal storage disorder caused by ceramidase deficiency that leads to accumulation of ceramide in various tissues. Mutations within ASAH1 encoding for ...acid ceramidase are responsible for the disease. Here we report two siblings with Farber disease who carry a novel V97G with the parents and a sister being asymptomatic carriers. The mutation site was found to be highly conserved among different species using ClustalW2 alignment. Functional prediction tools indicated the mutation to be pathogenic. Electron microscopy based ultrastructural studies using skin biopsy showed inclusion of enlarged lysosomes and presence of the zebra bodies. The T1 weighted magnetic resonance images of the brain indicated diffuse loss of the deep white matter volume predominantly along the occipital horns of the lateral ventricle with subsequent facet dilatation of the supratentorial and infratentorial ventricular system. This is the first report of a detailed clinical and molecular analysis of cases with Farber disease from Saudi Arabia.
Whereas many genes associated with intellectual disability (ID) encode synaptic proteins, transcriptional defects leading to ID are less well understood. We studied a large, consanguineous pedigree ...of Arab origin with seven members affected with ID and mild dysmorphic features. Homozygosity mapping and linkage analysis identified a candidate region on chromosome 17 with a maximum multipoint logarithm of odds score of 6.01. Targeted high-throughput sequencing of the exons in the candidate region identified a homozygous 4-bp deletion (c.169_172delCACT) in the METTL23 (methyltransferase like 23) gene, which is predicted to result in a frameshift and premature truncation (p.His57Valfs*11). Overexpressed METTL23 protein localized to both nucleus and cytoplasm, and physically interacted with GABPA (GA-binding protein transcription factor, alpha subunit). GABP, of which GABPA is a component, is known to regulate the expression of genes such as THPO (thrombopoietin) and ATP5B (ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide) and is implicated in a wide variety of important cellular functions. Overexpression of METTL23 resulted in increased transcriptional activity at the THPO promoter, whereas knockdown of METTL23 with siRNA resulted in decreased expression of ATP5B, thus revealing the importance of METTL23 as a regulator of GABPA function. The METTL23 mutation highlights a new transcriptional pathway underlying human intellectual function.
Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic ...heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency.
A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic.
These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.
Abstract Congenital disorders of glycosylation are often associated with muscle weakness in apparent isolation or as part of a multi-systemic disorder. We report here the clinical and pathological ...features resulting from a homozygous mutation of ALG2 in an extended family. Phenotypic heterogeneity is observed among the small cohort of patients reported to date and is highlighted by our study. Linkage analysis, homozygozity mapping and whole exome sequencing followed clinical and pathological characterization of patients who presented with a congenital limb girdle pattern of weakness with no ocular or bulbar involvement. Nerve stimulation studies were consistent with a congenital myasthenic syndrome. Severity and progression of disease was variable. Muscle biopsies showed myopathic features, ragged red fibers and a sub-sarcolemmal accumulation of structurally normal mitochondria. Whole exome sequencing revealed an indel mutation c.214_224delGGGGACTGGCTdelinsAGTCCCCG, p.72_75delGDWLinsSPR in exon 1 of ALG2 . Mutation of ALG2 manifested as a limb girdle pattern of muscle weakness with defects at both the neuromuscular junction and sarcomere. In addition the accumulation and distribution of mitochondria in the diseased muscle and the presence of ragged red fibers were supportive of a mitochondrial myopathy. ALG2 mutation results in a heterogeneous phenotype and care should be taken in categorization and treatment of these patients.
Five affected individuals with syndromic tremulous dystonia, spasticity, and white matter disease from a consanguineous extended family covering a period of over 24 years are presented. A positional ...cloning approach utilizing genome-wide linkage, homozygozity mapping and whole exome sequencing was used for genetic characterization. The impact of a calmodulin-binding transcription activator 2, (CAMTA2) isoform 2, hypomorphic mutation on mRNA and protein abundance was studied using fluorescent reporter expression cassettes. Human brain sub-region cDNA libraries were used to study the expression pattern of CAMTA2 transcript variants.
Linkage analysis and homozygozity mapping localized the disease allele to a 2.1 Mb interval on chromosome 17 with a LOD score of 4.58. Whole exome sequencing identified a G>A change in the transcript variant 2 5'UTR of CAMTA2 that was only 6 bases upstream of the translation start site (c.-6G > A) (NM_001171166.1) and segregated with disease in an autosomal recessive manner. Transfection of wild type and mutant 5'UTR-linked fluorescent reporters showed no impact upon mRNA levels but a significant reduction in the protein fluorescent activity implying translation inhibition.
Mutation of CAMTA2 resulting in post-transcriptional inhibition of its own gene activity likely underlies a novel syndromic tremulous dystonia.
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