Multiplex epithelium dysfunction due to CLDN10 mutation: the HELIX syndrome.

PurposeWe aimed to identify the genetic cause to a clinical syndrome encompassing hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (HELIX syndrome), and to comprehensively delineate the phenotype.MethodsWe performed homozygosity mapping, whole-genome sequencing, gene sequencing, expression studies, functional tests, protein bioinformatics, and histological characterization in two unrelated families with HELIX syndrome.ResultsWe identified biallelic missense mutations (c.386C>T, p.S131L and c.2T>C, p.M1T) in CLDN10B in six patients from two unrelated families. CLDN10B encodes Claudin-10b, an integral tight junction (TJ) membrane-spanning protein expressed in the kidney, skin, and salivary glands. All patients had hypohidrosis, renal loss of NaCl with secondary hyperaldosteronism and hypokalemia, as well as hypolacrymia, ichthyosis, xerostomia, and severe enamel wear. Functional testing revealed that patients had a decreased NaCl absorption in the thick ascending limb of the loop of Henle and a severely decreased secretion of saliva. Both mutations resulted in reduced or absent Claudin-10 at the plasma membrane of epithelial cells.ConclusionCLDN10 mutations cause a dysfunction in TJs in several tissues and, subsequently, abnormalities in renal ion transport, ectodermal gland homeostasis, and epidermal integrity.

The M694I/M694I genotype: A genetic risk factor of AA-amyloidosis in a group of Algerian patients with familial Mediterranean fever.

Familial Mediterranean fever (FMF, OMIM 249100) is the most common hereditary fever, resulting from mutations in MEFV. FMF is characterized by episodic febrile attacks and polyserositis. Renal AA-amyloidosis is a major complication, which often leads to end-stage renal disease in untreated patients. The data about the renal AA-amyloidosis secondary to FMF are scarce in North African countries and non-existent in Algeria. We aimed to investigate the MEFV mutations associated with this complication in an Algerian patient cohort. Molecular analysis included 28 unrelated Algerian FMF patients with ascertained amyloidosis, 23 of them were symptomatic and 5 were asymptomatic. For this study, a group of 20 FMF patients without renal amyloidosis were selected as controls according to their age, disease onset and disease duration. The mutations were detected by sequencing exon 10 of MEFV. A total of 87.5% (49/56) mutant alleles were identified in 27/28 analyzed patients; p.M694I was predominant and appeared with an allele frequency of 62.5%, followed by p.M694V (17.85%), p.M680I (5.35%) and p.I692Del (1.78%). Remarkably, only p.M694I mutation was observed among the asymptomatic patients. The M694I/M694I genotype, identified in 14/27 (52%) patients, was significantly associated with the development of amyloidosis compared to group of controls (p = 0.022). This study did not link the M694V/M694V genotype to the renal complication despite the fact that it has been observed only in the patients with amyloidosis (3/27; 11%) (p = 0.349). The association of other identified genotypes to this complication was statistically insignificant. The progression of amyloidosis led to end-stage renal disease in 14 patients with 6 deaths. This study shows that p.M694I homozygosity is a potential genetic risk factor for the development of renal AA-amyloidosis in Algerian FMF patients.

Interleukin-1 receptor antagonist deficiency with a novel mutation; late onset and successful treatment with canakinumab: a case report.

INTRODUCTION: Interleukin-1 receptor antagonist deficiency is a rare autoinflammatory disease involving neonatal onset of pustulosis, periostitis, and sterile osteomyelitis. The underlying genetic abnormality involves a recessive mutation in IL1RN, which encodes interleukin-1 receptor antagonist. In this case report, we describe a case of a 12-year-old Turkish girl who initially was presented at 1 year of age, older than previously reported children with interleukin-1 receptor antagonist deficiency, and with a novel mutation, p.R26X, in ILR1N. CASE PRESENTATION: Our patient developed pustular cutaneous lesions at 1 year of age. At the age of 12 years, she was hospitalized for arthralgia of her knees, elbows, and ankles and arthritis of the left knee, with simultaneous pustular cutaneous lesions. She was admitted to the intensive care unit because of septicemia and respiratory insufficiency during follow-up. A skin biopsy of hyperpigmented lesions demonstrated neutrophil infiltration in the epidermis and subepidermal pustular dermatosis. Interleukin-1 receptor antagonist deficiency was suspected, and genetic analysis revealed a homozygous mutation (p.R26X) in IL1RN, which led to a diagnosis of interleukin-1 receptor antagonist deficiency. Treatment with canakinumab (recombinant human anti-human interleukin-1ß monoclonal antibody) 150 mg subcutaneously once every 6 weeks was initiated. Our patient did not experience further cutaneous lesions or arthritis. Her post-treatment inflammatory markers were normal; she gained weight; and she was able to walk independently. CONCLUSIONS: In this case report, we describe a patient with interleukin-1 receptor antagonist deficiency who responded excellently to canakinumab treatment. We believe more awareness is warranted for interleukin-1 receptor antagonist deficiency in children. It is possible that the mutation in our patient was a founder mutation that may lead to diagnosis of additional cases in Turkey.

A Novel Missense Mutation in SRD5A3 Causes Congenital Disorder of Glycosylation Type I (Cerebello-Ocular Syndrome)

Abstract A consanguineous Qatari family having an autosomal recessive disorder characterized by severe mental retardation, cerebellar vermis hypoplasia, retinal degeneration, optic nerve atrophy, ataxic gait, and seizures was studied for identification of the offending gene and mutation. Homozygosity mapping identified an 11.4 Mb critical interval at 4q12 to q13.2 that would contain the gene responsible for the disorder. Ten positional candidate genes were screened for pathogenic mutations, but none were identified. Next-generation exome sequencing in one affected individual identified a novel SRD5A3 missense mutation c.T744G/p.F248L, which was subsequently confirmed by Sanger sequencing, suggesting a congenital disorder of glycosylation type IQ defect. Isoelectric focusing of serum transferrin showed a type I pattern indicative of an .-glycan assembly defect. This is a novel pathogenic mutation and the first SRD5A3 missense mutation as all others are protein-truncating mutations.

PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders.

The frequent comorbidity of Autism Spectrum Disorders (ASDs) with epilepsy suggests a shared underlying genetic susceptibility; several genes, when mutated, can contribute to both disorders. Recently, PRICKLE1 missense mutations were found to segregate with ASD. However, the mechanism by which mutations in this gene might contribute to ASD is unknown. To elucidate the role of PRICKLE1 in ASDs, we carried out studies in Prickle1(+/-) mice and Drosophila, yeast, and neuronal cell lines. We show that mice with Prickle1 mutations exhibit ASD-like behaviors. To find proteins that interact with PRICKLE1 in the central nervous system, we performed a yeast two-hybrid screen with a human brain cDNA library and isolated a peptide with homology to SYNAPSIN I (SYN1), a protein involved in synaptogenesis, synaptic vesicle formation, and regulation of neurotransmitter release. Endogenous Prickle1 and Syn1 co-localize in neurons and physically interact via the SYN1 region mutated in ASD and epilepsy. Finally, a mutation in PRICKLE1 disrupts its ability to increase the size of dense-core vesicles in PC12 cells. Taken together, these findings suggest PRICKLE1 mutations contribute to ASD by disrupting the interaction with SYN1 and regulation of synaptic vesicles.

Mutations in prickle orthologs cause seizures in flies, mice, and humans.

Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution.

A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome.

Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.

Neutrophil dysfunction in a family with a SAPHO syndrome-like phenotype.

SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) is an inflammatory disorder of the bone, skin, and joints. We describe a family with multiple affected members who segregate a SAPHO syndrome-like phenotype, and we report the results of neutrophil studies and candidate gene analysis. We obtained written informed consent and a family history and reviewed medical records. We collected DNA and sequenced candidate genes, and we performed functional studies on neutrophils isolated from the proband and her mother. The pedigree segregated chronic osteomyelitis and cutaneous inflammation in a pattern that suggested an autosomal-dominant disorder. No coding sequence mutations were detected in PSTPIP1, PSTPIP2, LPIN2, SH3BP2, or NCF4. Analysis of neutrophil function in the proband, including nitroblue tetrazolium tests, myeloperoxidase assays, neutrophil chemotaxis, and neutrophil chemotaxis assays, revealed no identifiable abnormalities. However, an abnormality in the luminol, but not the isoluminol, respiratory burst assays following stimulation with phorbol myristate acetate (PMA) was detected in neutrophils isolated from the affected proband. Internal oxidant production was also reduced in the proband and her mother when neutrophils were treated with fMLP with or without platelet-activating factor, PMA alone, or tumor necrosis factor alpha alone. This family segregates a disorder characterized by chronic inflammation of the skin and bone. Functional differences in neutrophils exist between affected individuals and controls. The biologic significance of this defect remains unknown. Identification of the gene defect will help identify an immunologic pathway that, when dysregulated, causes inflammation of the skin and bone.

Autoinflammatory bone disorders.

PURPOSE OF REVIEW: This review provides an update on clinical, genetic, and immunologic aspects of the autoinflammatory bone disorders. RECENT FINDINGS: Chronic noninfectious inflammation of the bone is a clinical feature of both chronic recurrent multifocal osteomyelitis and (to a lesser degree) cherubism. The genes responsible for Majeed syndrome (LPIN2), murine chronic multifocal osteomyelitis (pstpip2), and cherubism (SH3BP2 and possibly PTPN11) have been identified. Murine models of both chronic recurrent multifocal osteomyelitis and cherubism have demonstrated that the bone inflammation is mediated by hematopoietically derived cells and can occur in the absence of a functioning adaptive immune system. As the immunologic defects become better defined, the cells of the myeloid lineage are emerging as the primary players. SUMMARY: Chronic multifocal osteomyelitis and cherubism are hereditary chronic inflammatory disorders in which bone is the primary inflammatory target. Recent genetic and immunologic discoveries demonstrate involvement of the innate immune system, which places these entities in the category of autoinflammatory disorders.

Chronic recurrent multifocal osteomyelitis: a concise review and genetic update.

Chronic recurrent multifocal osteomyelitis is an autoinflammatory disorder characterized by bone pain and fever, a course of exacerbations and remissions, and a frequent association with other inflammatory conditions. Because its etiology is largely unknown, the diagnosis is still based on clinical criteria; treatment is empiric and not always successful. The diagnosis is supported by the presence of osteolytic lesions with surrounding sclerosis apparent on radiographs, and silent asymptomatic lesions frequently appear on nuclear scans. The histologic findings in bone biopsies are nonspecific, showing inflammatory changes with granulocytic infiltration. Several observations suggest the contribution of genetic factors to the etiology of chronic recurrent multifocal osteomyelitis. Indeed, mutations in LPIN2 cause a syndromic form of chronic recurrent multifocal osteomyelitis known as Majeed syndrome, while mutations in pstpip2 cause a murine form of the disorder. The roles played by LPIN2 and the human homolog of pstpip2, PSTPIP2, in the etiology of chronic recurrent multifocal osteomyelitis are uncertain but are currently being investigated. We emphasize the need to validate diagnostic clinical criteria and develop new pathogenesis-based targeted therapy.

Familial mediterranean fever in Arabs.

Autoinflammatory diseases are a group of disorders characterised by seemingly unprovoked inflammation in the absence of high-titre autoantibodies or antigen-specific T cells, and include the hereditary periodic fever syndromes. Familial Mediterranean fever (FMF) is an archetypal autoinflammatory disorder, which is autosomal recessive and has a high prevalence in non-Ashkenazi Jews, Armenians, Turks, and Arabs. The classic clinical picture is recurrent acute short-lived febrile and painful attacks with variable periods of remission. In a subset of patients, the disorder is complicated by amyloidosis that leads to renal failure. The gene responsible for FMF--MEFV--has been identified and its role in inflammation is being assessed. There seems to be a distinctive clinical picture in Arab patients with FMF, and the range and distribution of MEFV mutations is different from that noted in other affected ethnic groups. Here, we discuss the clinical and molecular aspects of FMF in Arabs.

The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series.

OBJECTIVES: To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations in Arab patients. PATIENTS AND METHODS: The study was performed in the pediatric FMF clinic of Jordan University Hospital over a period of 4 years. Patients were referred by their physicians for diagnosis, management, genetic study, and counseling. A diagnosis of FMF was made according to published criteria. Screening for 5 mutations, namely M694V, V726A, M694I, M680I, and E148Q, was performed by amplification refractory mutation system (ARMS) for the first 4 and by restriction endonuclease testing for E148Q. RESULTS: Of the 407 unrelated patients investigated, 239 (59%) had 1 or 2 mutations and 168 (41%) had none of the studied mutations detected. Of those with mutations, 92 were homozygous, 53 were compound heterozygotes, 3 had complex alleles, and 91 patients had only 1 identifiable mutation. Of the mutations, M694V, V726A, M694I, M680I, and E148Q accounted for 38, 26, 14, 10 and 13%, respectively. Twelve of our patients developed the protracted febrile myalgia syndrome (PFMS) of whom 5 (42%) were homozygous for M694V. Only 2 developed chronic renal failure, both of whom were homozygous for M694V and were not on colchicine prophylaxis. However, 43 patients had a family history of chronic renal failure, and 15 (35%) were homozygous for M694V. CONCLUSIONS: Our data indicate that the 5 MEFV mutations are well distributed in Arabs. They also show that M694V is the most common mutation in Arab patients with FMF and seems to have an association with the development of amyloidosis and the PFMS. The high frequency of V726A, and the unique high frequency of M694I in Arabs compared with 3 other ethnic groups, are confirmed.

Familial mediterranean Fever and renal disease.

Familial Mediterranean Fever (FMF) is a genetic disorder frequently diagnosed among the Arabs. It is also prevalent among Jews, Armenians and Turks. The clinical picture consists of febrile and painful attacks such as joint or chest pain that differ in quality across patients and even within the same patient. The gene responsible for FMF, MEFV, has been cloned and mutations were identified within its coding sequence. It encodes a protein that is expected to be a down regulator of inflammation. The major renal involvement in FMF is the occurrence of amyloidosis that primarily affects the kidneys causing proteinuria and ending in death from renal failure. It can be treated by dialysis and renal transplantation, but can be prevented by a daily regimen of colchicine. Other renal manifestations of FMF are discussed.

Diversity in polyp pathology and distribution of Familial Juvenile Polyposis Syndrome.

OBJECTIVE: Juvenile polyposis syndrome is a rare autosomal dominant disorder with incomplete penetrance. The aim of this study was to review our experience with juvenile polyposis syndrome with emphasis on the diversity of polyp pathology and distribution and the recommended treatment. METHODS: Over the period January 1994 through February 2001, 10 family members were managed at Princess Basma Teaching Hospital, Irbid, Jordan. Two siblings with juvenile polyposis syndrome are discussed. RESULTS: The polyps were unusually concentrated in the rectum. In one patient the polyps were purely of the adenomatous type. The father suffered from non-polyposis colon cancer at the age of 35. CONCLUSION: Proctocolectomy and ileal pouch-anal anastomosis is recommended as the treatment of choice. Screening of juvenile polyposis syndrome patients and their relatives is emphasized for early detection of malignancy.