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PubMed2026

Immune dysregulatory disorders: perspective from solving a diagnostic odyssey.

PURPOSE OF REVIEW: Inborn errors of immunity (IEIs), once considered rare disorders characterized primarily by recurrent infections, are now recognized as a rapidly expanding group of diseases encompassing autoimmunity, autoinflammation, allergy, malignancy, and immune dysregulation. Advances in next-generation sequencing, functional immunology, and systems biology have revealed overlap between traditionally distinct disease categories and highlighted the complexity of genotype-phenotype relationships. RECENT FINDINGS: While this evolution has led to the discovery of hundreds of previously unrecognized disorders, it has also challenged conventional diagnostic paradigms and demonstrated how patients may have care spread across multiple specialties, without a clear medical home. These discoveries have also highlighted ongoing challenges translating scientific findings to the clinic including difficulties in accessing genomic testing, interpretation of variants of uncertain significance, impacts of incomplete penetrance and somatic mosaicism, and limited availability of specialized functional assays. Emerging computational approaches, including artificial intelligence, offer opportunities to accelerate diagnosis but cannot replace comprehensive clinical evaluation or longitudinal physician-patient relationships. SUMMARY: This perspective examines how the diagnostic odyssey for immune dysregulatory disorders has evolved, side-by-side with the changing framework for diagnosing rare immune diseases. We propose an integrated approach combining clinical phenotyping, genomics, functional validation, and multidisciplinary expertise to unite ongoing discovery between clinicians and scientists, diagnostics, and patient outcomes.

diagnostic odyssey↗
PubMed2000

Sequence conservation and expression of the sex-lethal homologue in the fly Megaselia scalaris.

Sex-lethal (Sxl) is Drosophila melanogaster's key regulating gene in the sex-determining cascade. Its homologue in Megaselia scalaris, the chromosome 3 gene Megsxl, codes for a protein with an overall similarity of 77% with the corresponding D. melanogaster sequence. Expression in M. scalaris, however, is very unlike that in D. melanogaster. Megsxl transcripts with a long ORF occur in both sexes. Differential splicing is conserved but not sex-specific. There are several splice variants, among them one is common to gonads and somatic tissues of all developmental stages investigated, one is specific for ovaries and embryos, and a third one is not found in ovaries. In the ovary, Megsxl is heavily transcribed in nurse cells and transported into eggs. These results suggest a non-sex-determining function during early embryogenesis; the presence of Megsxl RNA in testes and somatic tissues calls for other (or more) functions.

Age Factors↗
PubMed2026

EML4-ALK Variant-Specific Genetic Interactions Shape Lung Tumorigenesis.

UNLABELLED: Diverse fusions of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) are oncogenic drivers in lung adenocarcinoma. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. In this study, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that variant 3 (V3) is more oncogenic than variant 1 (V1). By using multiplexed genome editing and quantifying the effects of 29 putative tumor-suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor-suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor-suppressor gene alterations on the biology of oncogenic fusion-driven cancers. SIGNIFICANCE: EML4-ALK-driven lung cancer is treated as a uniform disease despite the presence of distinct fusion variants in patients. Our findings show that EML4-ALK variants are functionally distinct, which may have implications for the treatment of this cancer type and highlights the need to consider differences among variants of other oncogenic fusions.

Animals↗
PubMed1998

The olfactory adenylyl cyclase III is expressed in rat germ cells during spermiogenesis.

To identify the adenylyl cyclase (AC) genes expressed in mammalian germ cells, RT-PCR of testis and germ cell RNA was performed using degenerated primers based on the homologous region of the AC catalytic domain. This strategy yielded high-frequency amplification of a complementary DNA (cDNA) identical to type III AC (ACIII), a form previously identified as the major adenylyl cyclase expressed in the olfactory system. Ribonuclease protection studies confirmed that ACIII transcripts are present in germ cells, appear during the meiotic prophase, and accumulate during spermiogenesis. A Northern blot analysis performed on total testis RNA demonstrated the presence of a predominant transcript of 7.5 kb, suggesting that the ACIII expressed in germ cells may derive from a splicing variant different from the 4.5 kb transcripts expressed in somatic cells. To determine whether these RNAs are translated into a protein, Western blot analysis was performed using an antibody specific for the carboxyl terminus of ACIII. An immunoreactive protein of 170 kDa was detected in extracts from total testis and from germ cells. Immunofluorescence localization of this protein in the seminiferous tubules showed that ACIII was predominantly expressed in postmeiotic germ cells from round spermatids in the cap phase to maturing elongating spermatids. The ACIII antigen was located mostly on the acrosomal membrane rather than on the plasma membrane of developing spermatids. The spatial and temporal expression of ACIII in germ cells indicates a role of this AC in the acrosome formation. Together with the observation that members of the olfactory receptor family and an olfactory phosphodiesterase are expressed in spermatids, these findings suggest that a signal transduction system used in olfaction is also used during gamete development.

Adenylyl Cyclases↗
PubMed2006

Pharmacogenetics of alkylator-associated acute myeloid leukemia.

Therapy-related acute myeloid leukemia (t-AML) is a lethal late complication of alkylator chemotherapy. The genetic basis of susceptibility to t-AML is poorly understood. Both t-AML and de novo AML are complex genetic diseases, requiring cooperating mutations in interacting pathways for disease initiation and progression. Germline variants of these 'leukemia pathway' genes may cooperate with somatic mutations to induce both de novo and therapy-related AML. Several cancer susceptibility syndromes have been identified that cause an inherited predisposition to de novo and t-AML. The genes responsible for these syndromes are also somatically mutated in sporadic AML. We reason that germline polymorphism in any gene somatically mutated in AML could contribute to t-AML risk in the general population. Identification of these susceptibility alleles should help clinicians develop tailored therapies that reduce the relative risk of t-AML.

Alkylating Agents↗
PubMed1999

Psychological and social characteristics and precipitants of vomiting in children with cyclic vomiting syndrome.

A psychological etiology or predisposition for cyclic vomiting syndrome (CVS) has long been suspected. Much of the psychiatric literature to date has blamed patients or their families for the problem or focused on psychoanalytic interpretation to account for the syndrome. Thirty-two patients with CVS were compared with 64 age- and sex-matched controls. The patients had a higher incidence of psychological symptoms and migraine. On the Achenbach Child Behavior Checklist patients had higher internalizing, somatic complaints, and anxiety/depression scores. CVS is a migraine variant, with attacks usually precipitated by stress and intercurrent infections. The psychological characteristics of patients with CVS probably contribute to their vulnerability.

Adolescent↗
PubMed1978

[Early diagnosis of neoplasms].

Cancer is a generic term for a variant manifestation of life caused by genetic mutations of somatic cells. It is not only carcinogenesis which is basically a genetic phenomenon, but also tumor progression which can be influenced by various genetic factors. A group of tumors is known to be inherited in a Mendelian fashion. In addition a great number of single gene disorders is associated with the development of maligne tumors. The further study of these diseases will allow new insights into the fundamental mechanisms leading to clinical cancer. In this respect a series of immunodeficiency diseases is of particular interest. Several organ tumors which seem to occur more frequently in relatives of tumor patients are of practical importance. A more sophisticated classification of these tumors may illuminate their genetic behavior. The geneticist cannot only define groups of individuals with a high cancer risk, but he can identify genetic, e.g. chromosomal, aberrations of cancerous cells which enables him the early detection of neoplasia.

Chromosome Aberrations↗
PubMed2001

[Psychogenic neurotic depression in women (psychopathological and psychosomatic aspects)].

Examination of 85 female inpatients with psychogenic neurotic mood disorders aged from 18 to 48 years has found the following depression syndrome variants: asthenic (42 patients), anxiety (14), asthenoanxiety (15), anxiety-melancholic (14). Hypothymia both mildly or moderately expressed and psychosomatic disorders as functional disturbances of reproductive, nervous and cardiovascular systems, were found. These disturbances were qualified as somatoform disorders. The most typical was autonomic dystonia syndrome. During the course of depression, somatization of psychic disorders was increasing, being most distinct in asthenic variants.

Adolescent↗
PubMed1989

Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome.

The glycophorin A assay was used to estimate the frequency of mutations that accumulate in vivo in somatic cells of persons with Bloom's syndrome (BS). This assay measures the frequency in persons of blood type MN of variant erythrocytes that lack the expression of one allelic form of glycophorin A, presumably due to mutational or recombinational events in erythroid precursor cells. Samples of blood from persons with BS showed dramatic 50- to 100-fold increases in the frequency of variants of three types, those with a hemizygous phenotype, those with a homozygous phenotype, and those with what appears to be partial loss of the expression of one locus. The high frequency of homozygous variants, genetic evidence for altered allelic segregation of a specific biochemical locus, provides evidence for increased somatic crossing-over in vivo in BS. An increased generation of functional hemizygosity and homozygosity in their somatic cells may play an important role in the extreme cancer risk of persons with BS.

Adolescent↗
PubMed1987

A developmentally regulated isoform of 150,000 molecular weight neurofilament protein specifically expressed in autonomic and small sensory neurons.

Neurofilament heterogeneity has been demonstrated using a monoclonal antibody (CH1) specific for the 150,000 molecular weight neurofilament subunit. In the peripheral nervous system of adult rats CH1 stained selectively sympathetic and parasympathetic neurons and a subpopulation of small neurons in the sensory dorsal root ganglia. Somatic motor neurons and large neurons in dorsal root ganglia were completely unreactive. In contrast, the anti-neurofilament antibody iC8, directed against the 150,000 molecular weight subunit, labelled all peripheral nervous system neurons. The immunostaining pattern with both antibodies was unchanged by phosphatase treatment. These data indicate that two antigenically distinct variants of the 150,000 molecular weight neurofilament subunit exist in somatic and autonomic neurons of adult animals. In addition, the phosphatase treatment suggests that the antigen recognized by CH1 is not masked by phosphorylation. In contrast, all neurons were labelled by this antibody in the peripheral nervous system of newborn rats. It is suggested that CH1 identifies a fetal 150,000 molecular weight neurofilament polypeptide isoform whose expression is prevented by the growth of somatic neurons and is selectively maintained in autonomic and small sensory neurons.

Adrenergic Fibers↗
PubMed1981

Antibody diversity: somatic hypermutation of rearranged VH genes.

The immune response to phosphorylcholine in BALB/c mice has been well characterized. Amino acid sequence analyses of heavy-chain variable (VH) regions from 19 myeloma and hybridoma immunoglobulins binding phosphorylcholine show that 10 are identical (the prototype T15 VH sequence) and 9 are distinct variants differing by one to eight residues. A T15 VH DNA probe was used to isolate four closely related members of the T15 VH gene family, including one encoding the T15 VH sequence, from a sperm genomic library. A comparison of the protein and germline VH sequences suggested that most of the immune response to phosphorylcholine is derived from the T15 germline VH gene segment. The variant heavy chains from the M167 and M603 alpha immunoglobulins differ in their VH protein sequences from T15 by eight and three residues, respectively. We analyzed the somatic variability in and around the coding regions of these two variant VH genes by comparing them with the corresponding regions of the appropriate germline gene segments. The somatic variation has three properties: it is extensive and is found in flanking as well as coding sequences (for example, at least 44 substitutions for the M167 sequence and 10 substitutions for the M603 sequence); in the coding regions, it includes many silent as well as replacement substitutions; and it is focal in nature and centered around the rearranged VH genes. Although the mutations extend into the neighboring upstream and downstream flanking sequences, sequences approximately 5 kb upstream and downstream from the VH genes show no substitutions. Moreover, the associated heavy-chain constant genes (C alpha) from both variant alpha genes are unaltered, indicating that a closely linked and coexpressed gene is unmutated. We conclude that this somatic variation is generated by a special hypermutational mechanism highly localized in its site of execution and highly restricted in its time of operation during B-cell development.

Animals↗
PubMed1994

A comparison of delusional and nondelusional body dysmorphic disorder in 100 cases.

A controversial issue that was debated for DSM-IV is whether body dysmorphic disorder (BDD)--a preoccupation with an imagined defect in appearance--can be psychotic. BDD is classified separately from its delusional counterpart (delusional disorder, somatic type) in DSM-IV, but does it have a psychotic variant that overlaps with, and may even be the same diagnostic entity as, its delusional disorder variant? One hundred consecutive patients with DSM-III-R-defined BDD or its delusional variant were assessed with a semistructured interview, the Structured Clinical Inverview for DSM-III-R, and a modified version of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The 48 patients with nondelusional BDD were compared with the 52 patients with delusional BDD (i.e., delusional disorder, somatic type). The two groups did not differ significantly in terms of most variables examined, including demographics, phenomenology, course, associated features, comorbidity, and treatment response. Thus, BDD may have a psychotic subtype that significantly overlaps with, and may even be the same disorder as, its delusional disorder variant. However, delusional subjects had higher total scores on the modified Y-BOCS, suggesting that the delusional variant of BDD may be a more severe form of the disorder. Although preliminary, these findings have implications for BDD's treatment and classification, suggesting that inclusion of a delusional (psychotic) subtype of BDD should be considered for future editions of DSM.

Adolescent↗
PubMed2026

The role of SYNE1/2 variants as a potential predisposition factor for the onset of endometriosis.

Endometriosis (EM) is a chronic, inflammatory gynaecological disorder defined by the presence of endometrial-like tissue outside the uterine cavity, most frequently affecting the ovaries, peritoneum, and uterosacral ligaments. Despite its prevalence and the significant impact on life quality, EM is often underdiagnosed, with an average delay of about nine years, particularly affecting adolescents and young women. The complex aetiology involves genetic, environmental, and immune factors, with whole-exome sequencing (WES) emerging as a potential tool for identifying relevant genetic variants. Research indicates that innate immune dysfunction, mechanotransduction, and epithelial-to-mesenchymal transition promote endometrial cell migration and lesion formation, processes regulated by nuclear envelope integrity and cytoskeletal dynamics. The LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, specifically Nesprin-1 and Nesprin-2, encoded by SYNE1 and SYNE2, is crucial for these processes. Genome-wide studies have linked SYNE genes to EM risk, showing downregulation in affected patients, and rare variants in these genes have been identified, though their functional implications are still unclear. To this purpose, WES was performed on 204 EM patients to identify rare (MAF <0.1%), damaging variants in SYNE1/2. Primary endometriotic cells (EMCs) were isolated from ovarian lesions of variant carriers (n=4) and wild-type (WT) non-carrier controls (n=4). Functional characterization included somatic WES, RT-qPCR, Western blot, confocal immunofluorescence, and Transwell migration assays. WES identified 11 rare, likely damaging SYNE1/2 variants in 12 patients. Immunofluorescence revealed a distinct protein mislocalization, WT EMCs displayed physiological Nesprin-2 confinement at the nuclear envelope, whereas variant carriers exhibited a diffuse cytoplasmic distribution polarized along actin stress fibres. We demonstrated that SYNE1/2 mutated EMCs had a markedly higher migratory capacity compared to WT controls. Here, in vitro experiments demonstrated, for the first time, the involvement of Nesprin-2 in endometrial cell migration, supporting a mechanistic link between nuclear-cytoskeletal disruption and the invasive phenotype of endometriotic cells (EMCs). These findings provide new insights into EM pathogenesis and highlight SYNE2 as a promising molecular marker for improved diagnosis and disease management.

Humans↗
PubMed1991

The highly variable pentameric repeats of the AT-rich germline limited DNA in Parascaris univalens are the telomeric repeats of somatic chromosomes.

We have characterized the organization of the germline limited DNA of P. univalens by means of sequence analysis. The repeat unit of this satellite DNA is the pentanucleotide 5'TTGCA, although there is a high degree of sequence variation. Repeat variants are not arranged in tandem but in a disperse, nonrandom manner. In the somatic genome which arises from the germline genome through extensive genomic rearrangement early in development, copies of these pentamers represent the telomeric repeats, indicated by their sensitivity to Bal 31 and their presence in a somatic endlibrary. Unlike telomeric sequences from other species the P. univalens telomeres do not display consecutive guanines and no strand bias for that base, recently suggested as universal features of eukaryotic telomeres. Investigation of fragments that carry pentameric repeats along with sequences of different type identifies a 5 bp consensus sequence at the junction point. We suggest a model in which pentameric repeats originate via amplification by a terminal transferase (telomerase) in both the germline and the somatic genome.

Animals↗
PubMed1999

Functional reassessment of P16 variants using a transfection-based assay.

CDKN2A appears to be the major melanoma susceptibility gene, and is also mutated/deleted in sporadic tumours of various types including melanoma. Thus far most approaches to assessing the functionality of mutations in this gene have used in vitro methods such as CDK4 binding and kinase inhibition assays, with sometimes disparate conclusions about functional significance of some variants between studies. We have used a melanoma cell line (MM96L) with no functional p16, as the basis for a "semi-in vivo" transfection-based assay for exogenous p16 functionality based on the growth parameters of the cells and the behaviour of variant proteins after transfection of different CDKN2A cDNAs. Colony counts performed on these transfectants revealed that all but the wild type, + 24 bp ad A148T variants have a diminished ability to inhibit cell growth. All other variants detected either constitutionally in familial melanoma patients (I49T, R87P, G101W and V126D) or somatically in melanomas (N71S, and P81L), appeared functionally impaired in this assay. This diminution of function was independent of CDK4 and CDK6 binding ability. Furthermore, the predominant localization of these variants within the cell was different from that of wt p16. This mislocalization may provide an explanation for their lack of function, or alternatively, it may also be an indicator that the cells are processing unstable, misfolded p16 proteins. This novel assay for assessment of functionality of p16 variants may better reflect the role of some of these mutations in vivo, and as such is a useful adjunct to other in vitro assays.

Cell Nucleus↗
PubMed2002

Detection of mitochondrial DNA alterations in the serum of hepatocellular carcinoma patients.

PURPOSE: Somatic mutations in mitochondrial DNA (mtDNA) have recently been detected in various cancers. These mutations could possibly be detected in serum because mtDNA has a higher copy number than nuclear DNA. Thus, we examined genetic alterations in the D-loop region of mtDNA in hepatocellular carcinoma (HCC) patients. EXPERIMENTAL DESIGN: Fifty patients with HCC were investigated in this study. Somatic mutations in the D-loop region of tumor mtDNA were screened by direct sequencing, and then the paired serum samples were investigated using mutation-specific mismatch ligation assay. RESULTS: Fifteen of 100 sequence variants that were detected in tumor mtDNA have not been recorded previously. True somatic mutations in the D-loop region were detected in 17 of 50 patients (34%). Subsequent screening for paired serum by mismatch ligation assay revealed that 5 of 15 paired serum samples (33%) contained the same mutations as primary tumors. CONCLUSIONS: mtDNA mutation may be a novel tumor marker of HCC and may prove effective for detection of tumor DNA in the serum.

Base Pair Mismatch↗
PubMed1997

Germ cell-somatic cell dichotomy of a low-density lipoprotein receptor gene family member in testis.

Members of the low-density lipoprotein receptor (LDLR) supergene family interact with a large number of diverse ligands. One of the relevant receptors is the recently characterized LDLR relative with eight ligand-binding repeats, termed LR8, which exists in two splice variant forms. The gonads, relying on receptor-mediated lipoprotein supply for steroidogenesis, and on interplay of germ cells with somatic cells, provide a particularly attractive setting to study details of the expression of LR8. Here we show by polymerase chain reactions and Northern analysis, as well as by in situ hybridization, that the longer of the two splice variants (LR8+), containing an additional region defining an O-linked sugar domain, is produced in the somatic cells of chicken testis, whereas the shorter form lacking this domain (LR8-) is expressed in the male germ cells. Interestingly, as shown by transcript analysis and at the functional level by ligand blotting, LR8- expression in the spermatoids increases with germ cell maturation, but is absent from ejaculated sperm. This constitutes a scenario reminiscent of the situation in growing vitellogenic oocytes, which express very high levels of LR8-, but lack the receptor following ovulation. Thus, the cell-specific expression of different LR8 splice variants may relate to the requirements of extensive communication and cooperation between germ cells and somatic cells in the gonads.

Alternative Splicing↗
PubMed1992

Expression of platelet-derived growth factor-independent phenotypes in BALB/c 3T3 cell variant with high susceptibility to chemically or physically induced neoplastic cell transformation: dissociation from activation of protein kinase C.

A31-I-13, a clonal cell variant of nontransformed BALB/c 3T3 that is highly susceptible to chemically or physically induced malignant cell transformation but is not sensitive to cell killing or susceptible to induced somatic cell mutation compared with another less transformation-susceptible A31-I-1 cell variant, was previously found to be constitutively competent [platelet-derived growth factor (PDGF)-independent] to synthesize DNA (M. Tatsuka et al., J. Cell. Physiol., 139: 18-23, 1989). The present study has demonstrated that density-arrested, quiescent A31-I-13 cells autonomously exhibit disruption of actin filamentous bundles and perturbations of dynamic morphology. PDGF induced these cytoskeletal modulations in quiescent A31-I-1 cells, which require PDGF for the induction of DNA synthesis. Furthermore, the cytoskeletal modulations of quiescent A31-I-13 cells were not accompanied by an increased production of plasminogen activators, activation of protein kinase C, or phosphorylation of a Triton X-100-soluble protein (molecular weight, 90,000) known as 80K, a major substrate for protein kinase C. However, these modulations were accompanied by the tyrosine phosphorylation of Triton X-100-insoluble (cytoskeletal) proteins with molecular weights of 24,000, 32,000-33,000, and 36,000. These Triton X-100-insoluble proteins, as well as the 80K protein, were phosphorylated by the exposure of quiescent A31-I-1 cells to PDGF. Thus the pathway for producing the transformation-susceptible phenotype in A31-I-13 appears to coincide with the PDGF signaling pathway but does not involve the protein kinase C pathway.

3T3 Cells↗