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PubMed1993

Novel missense variants of prion protein in Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome.

We found 3 novel missense variants in the open reading frame of the prion protein (PrP) gene. The codon 105 point mutation (proline to leucine) was found on a codon 129 (Valine) PrP allele in 4 patients from 3 different Japanese families with Gerstmann-Sträussler syndrome. The codon 180 variant PrP (valine to isoleucine) was found in Creutzfeldt-Jakob disease (CJD) patients with a similar clinical course to that of codon 178 mutation. The codon 232 variant PrP (methionine to arginine) was documented in the CJD patients with typical clinical and pathological findings. These variant PrP molecules were not detected in 200 normal Japanese PrP alleles. PrP has a large repertoire of variant forms, and each primary structure of PrP corresponds to the distinct phenotype of prion diseases.

Base Sequence↗

PubMed2026

A novel hemizygous missense variant in the BEND2 gene is associated with nonobstructive azoospermia.

Nonobstructive azoospermia (NOA), the most severe form of male infertility, frequently arises from genetic defects that disrupt spermatogenesis. In this study, a novel hemizygous missense variant (NM_001184767.2 [c.G1069A; p.V357I]) is identified in the X-linked BEN domain-containing 2 ( BEND2 ) gene of a patient with NOA characterized by spermatocyte maturation arrest. Whole-exome sequencing and Sanger validation confirmed that this rare variant is absent in fertile controls and that no pathogenic variants were detected in established NOA genes. Computational analysis predicted potential structural alterations via AlphaFold modeling, leading to the hypothesis that the ability of BEND2 to recognize genomic targets may be compromised. The patient's phenotype phenocopies the meiotic arrest observed in Bend2 -knockout mice. Expression profiling confirmed predominant BEND2 transcription in human and mouse testes, peaking in early spermatocytes and coinciding with meiotic initiation, with reduced transcript levels detected in the proband's peripheral blood compared with those in an obstructive azoospermia control. This study reports a pathogenic BEND2 variant associated with NOA with spermatocyte arrest, highlighting its critical role in human meiosis and expanding the genetic etiology of male infertility.

Adult↗

PubMed2026

Analysis of structure and conservation for supporting functional evaluation of PMS2 missense variants.

Germline defects in mismatch repair (MMR) genes are known to significantly increase the risk of developing certain types of cancers, notably colorectal and endometrial cancers. These conditions are characterized under Lynch syndrome. Accurate diagnosis of this predisposition, along with meaningful predictive testing for family members, necessitates the identification of pathogenic variants. However, classifying small coding genetic variants identified in cancer patients is very challenging, specifically in the case of PMS2 variants, since PMS2 pathogenic variants display a lower penetrance and less severe phenotype and therefore a lower tumor burden in affected families. We have assembled clinical data on four PMS2 missense variants of uncertain significance (VUS) identified in 23 patients (p.(Asp286Gly), p.(Asn335Ser), p.(Ile679Thr) and p.(Arg799Trp)). For these variants, functional testing was performed (RNA splicing, protein stability and catalytic activity). Since many protein ortholog sequences and accurate predictive models from AlphaFold2 are available, we also included a systematic analysis of residue conservation and structural role (ConStruct assessment). Overall, our findings indicate that p.(Asp286Gly) and p.(Arg799Trp) behave similarly to wild-type PMS2 and are thus probably neutral. In contrast, p.(Asn335Ser) and p.(Ile679Thr) conferred defects in protein expression or MMR activity. These could be explained by the relevant roles of these amino acids in MLH1-PMS2-N-terminal dimerization (p.Asn335) and C-terminal dimerization (p.Ile679). Our data thus suggest that p.(Asp286Gly) and p.(Arg799Trp) are benign, while the tumor risk in the other two variants remains to be established. Taken together, we suggest roadmaps for the individualized evaluation of difficult uncertain variants by comprising information from all available sources.

Humans↗

PubMed2000

Five missense variants in the amino-terminal domain of the glucocorticoid receptor: no association with puerperal psychosis or schizophrenia.

Steroid hormone administration causes behavior changes in many and psychosis in a few. The clinical features suggest that genetic variants of the glucocorticoid receptor or cofactors could produce susceptible subpopulations who react adversely to hormonal cascades. To investigate this possibility, coding and splice site sequences of the glucocorticoid receptor were scanned for single nucleotide polymorphisms in genomic DNA samples from 100 schizophrenics (86 Caucasians and 14 African-Americans) and 40 Caucasians with puerperal psychosis. Five amino acid substitutions were found in the amino-terminal domain at frequencies of 0.6 to 3.8% in Caucasians: R23K, F29L, L112F, D233N, and N363S. In addition, four silent nucleotide changes were found: E22E, K293K, D677D, and N766N; a transversion in intron 4 occurred beyond the splice junction. None of these variants can be linked to these disorders at present. However, the N363S variant contributes a new potential phosphorylation site and has been associated with increased body mass and reduced bone mineral density [Huizenga et al., 1998], so it is possible that the other missense variants confer traits that currently are unrecognized. Comparisons to natural glucocorticoid receptor mutants in the familial glucocorticoid resistance syndrome and steroid resistant leukemias suggest that amino acid substitutions at highly conserved residues may cause severe functional defects and serious illness, while changes at less conserved sites produce lesser alterations and milder disease.

Amino Acid Sequence↗

PubMed1999

Missense variants in the human peroxisome proliferator-activated receptor-gamma2 gene in lean and obese subjects.

The peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) is almost uniquely expressed in adipose tissue and is of major importance for fat cell differentiation and lipid metabolism. This study was undertaken to assess whether two missense variants in the PPARgamma2 gene are associated with early-onset obesity. A previously described polymorphism encoding for an amino acid exchange in codon 12 (Pro12Ala) was detected with allele frequencies of 0.13 in 296 markedly obese children and adolescents and 0.14 in 130 lean individuals. A Pro115Gln variant, which had been linked to obesity in Germans in a previous association study, was not detected in any of our obese or lean subjects, who are also of German origin. We conclude from our data that these two variants in the PPARgamma2 gene are unlikely to contribute to the high prevalence of early-onset obesity.

Adolescent↗

PubMed1990

Creutzfeldt-Jakob disease patients with congophilic kuru plaques have the missense variant prion protein common to Gerstmann-Sträussler syndrome.

Congophilic kuru plaques, one of the pathological hallmarks in kuru and Gerstmann-Sträussler syndrome, are sometimes present in patients with Creutzfeldt-Jakob disease (CJD). The congophilic kuru plaques are composed partly of a host-encoded prion protein, and a missense variant prion protein with the codon 102 proline-to-leucine change (Leu102) is commonly present in patients with Gerstmann-Sträussler syndrome. To investigate the relationship between this syndrome and CJD with congophilic kuru plaques, we made a sequence analysis of the prion protein gene from patients with CJD, with or without congophilic kuru plaques. We found no alterations other than the Leu102 change, common to Gerstmann-Sträussler syndrome, in one of the prion protein alleles of the patient with congophilic kuru plaques. In the prion protein genotype analysis of other patients with CJD, the Leu102 allele was revealed to be carried heterozygously by 6 of 7 patients who had CJD with congophilic kuru plaques, yet no patient with CJD without congophilic kuru plaques had this allele. Interestingly, the Leu102 allele was also carried by some unaffected relatives of 3 patients with CJD with congophilic kuru plaques but with no apparent familial occurrence of a similar neurological disorder. Our findings show that CJD with congophilic kuru plaques should be categorized as belonging to Gerstmann-Sträussler syndrome, not CJD, and also suggest that the variant prion protein with Leu102 is closely related to the amyloidogenesis seen in subjects with congophilic kuru plaques.

Adult↗

PubMed2026

De Novo TRIO Missense Variants Disrupt Ras-GEF Domains and Cause Congenital Ventriculomegaly and Hydrocephalus.

Congenital hydrocephalus (CH), characterized by congenital ventriculomegaly (CV), affects approximately 0.5-1 per 1000 live births and is a common cause of pediatric neurosurgical intervention, yet its genetic architecture remains incompletely defined. We report a child with syndromic CH requiring cerebrospinal fluid diversion who harbored a pathogenic de novo missense variant in TRIO (c.3232C > T; p.(Arg1078Trp)), a gene previously associated with autosomal dominant neurodevelopmental disorders featuring variable head circumference. This case prompted systematic evaluation of TRIO variation in our CV/CH cohort (2,697 patient-parent trios) using exome sequencing. We identified five additional unrelated probands with de novo TRIO variants, including two novel substitutions affecting the same residue within the Ras-GEF1 domain (p.(Glu1299Lys) and p.(Glu1299Gly)), yielding significant gene-level enrichment for protein-damaging de novo variants (adjusted p = 6.12 × 10-5). All affected individuals exhibited CV, frequently accompanied by developmental delay and additional structural brain abnormalities. In silico structural modeling predicted that associated variants destabilize critical TRIO Ras-GEF domains required for Rho GTPase activation. Analysis of single-nucleus transcriptomic data from the developing human neocortex revealed enrichment of TRIO expression in multipotent progenitor populations. A systematic literature review identified six additional individuals with TRIO de novo variants and reported CV or CH, including an unrelated patient with the same p.(Arg1078Trp) substitution. Together, these findings expand the phenotypic spectrum associated with pathogenic TRIO variation to include CV/CH and support TRIO as a clinically relevant gene in the genetic evaluation of syndromic CV/CH patients.

Humans↗

PubMed2025

Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.

Recognition of specific DNA sequences by transcription factors (TFs) is a key step in transcriptional control of gene expression. While most forkhead (FH) TFs bind either an FKH (RYAAAYA) or an FHL (GACGC) recognition motif, some FHs can bind both motifs. Mechanisms that control whether an FH is monospecific vs. bispecific have remained unknown. Screening a library of 12 reference FH proteins, 61 naturally occurring missense variants including clinical variants, and 22 designed mutant FHs for DNA-binding activity using universal ("all 10-mer") protein-binding microarrays revealed non-DNA-contacting residues that control mono- vs. bispecificity. Variation in non-DNA-contacting amino acid residues of TFs is associated with human traits and may play a role in the evolution of TF DNA-binding activities and gene regulatory networks.

Humans↗

PubMed2026

Anti-inflammatory activity of an IL-6 missense variant against crystal-induced inflammatory response.

Interleukin-6 (IL-6) has an important modulator effect on inflammation and immunity and is involved in the progression of nephrolithiasis (kidney stone). However, whether IL-6 genetic variants affect the pathogenesis of kidney stones remains unclear. The present study conducted a combined investigation of candidate gene-driven screening and systematic screening on whole exome sequencing data from 28 patients of calcium oxalate stones, identifying a non-synonymous single nucleotide polymorphism (SNP) rs13306435 in IL-6 as a candidate research locus, which was further validated using HRM genotyping in an expanded cohort comprising 241 cases and 229 healthy subjects. Western blotting and qRT-PCR were used to assess the effects of this variant on crystal-induced inflammation, while molecular dynamics simulation was employed to analyze structural alterations in the receptor binding complex. In individuals aged ≤40 years, the A allele of rs13306435 was nominally associated with a reduced risk of stone formation, but no association was observed for the whole population. This missense variant causes an aspartate-to-glutamate substitution (D/E), inhibiting calcium oxalate monohydrate (COM)-triggered JAK2/STAT3 activation and inflammatory responses. However, it decreased the binding energy of IL-6/IL-6R/gp130 complex by increasing hydrogen bonds and salt brigdge at remote interfaces, suggesting that enhanced receptor binding does not necessarily translate to increased downstream signaling. Although this variant is not associated with general stone susceptibility, it exhibits notable anti-inflammatory activity by attenuating COM-induced JAK2/STAT3 activation and may influence the progression of stones through this pathway. These findings provide new insights into the role of anti-inflammatory mechanisms in nephrolithiasis.

Humans↗

PubMed1991

A prion protein missense variant is integrated in kuru plaque cores in patients with Gerstmann-Sträussler syndrome.

Kuru plaques are the pathologic hallmark in Gerstmann-Sträussler syndrome (GSS). To demonstrate that prion protein (PrP) is a component of kuru plaque cores, we fractionated and sequenced kuru plaque core derived peptides, following digestion with Achromobacter lyticus protease I. We identified 3 PrP-derived peptides by reverse-phase high-performance liquid chromatography and found a fragment of digests derived from a missense variant of PrP. The variant PrP was also present in the prion rod fraction in patients with GSS. This substitution may play a major role in cerebral amyloidogenesis.

Amino Acid Sequence↗

PubMed2002

Involvement of ATM missense variants and mutations in a series of unselected breast cancer cases.

It has been proposed that women carrying heterozygous mutations of the ATM gene could be at increased risk of developing breast cancer. However, data in the literature are contrasting and no firm conclusion has been reached. Our aim was to verify whether ATM inactivation could play a role in breast tumor development. Following the classical tumor suppressor inactivation scheme, tumors showing loss of heterozygosity (LOH) at the ATM locus should present an increased proportion of mutated ATM forms. We screened a cohort of 173 nonselected primary breast tumors for LOH in a 4 cM region at 11q23 spanning the ATM gene. We analyzed 25 tumors presenting LOH within the ATM locus for mutations in the ATM coding sequence using an RT-PCR-SSCP approach. Five patients were found to bear a coding missense variant, out of which four corresponded to a frequent polymorphism in exon 39. One patient presented a previously unreported variant in exon 19 (2614C>T) resulting in a nonconservative change (Pro>Ser) at aa 872. This variant was not found in any of the other 172 patients nor in 63 healthy controls tested, indicating that it is a rare ATM variant. LOH involved the ATM wild-type allele in the tumor presenting variant 2614. However, because the ATM gene presents a relatively large number of rare coding polymorphism it is difficult, in the absence of familial data, to be conclusive on the significance of this variant. Searching for further variants in exons 19 and 39 in the whole set of 173 breast tumors, we found one tumor showing an acquired deletion of four bases in the ATM gene. Somatic mutations affecting the ATM gene thus seem rare in breast cancer. In our cohort of breast cancer patients, tumors presenting LOH at the ATM locus did not show an increased frequency of sequence variants. Furthermore, allelic imbalance profiles in a 4-cM region of chromosome arm 11q spanning the ATM locus revealed that hot spots of LOH were more likely to correspond to a region localized telomeric to the gene. Therefore, these data suggest that other target genes for genetic inactivation exist in the 11q23 region.

Alleles↗

PubMed1997

Molecular screening of the human melanocortin-4 receptor gene: identification of a missense variant showing no association with obesity, plasma glucose, or insulin.

Disruption of the melanocortin-4 (MC-4) receptor gene in mice results in maturity-onset obesity, hyperinsulinaemia and hyperglycaemia. These phenotypes are characteristic of human obesity that frequently accompanies non-insulin-dependent diabetes. It is therefore possible that human MC-4 receptor gene mutations contribute to human obesity. To test this possibility, we examined by DNA sequencing the entire coding region of the human MC-4 receptor gene in 40 morbidly obese (BMI > 35 kg/m2) white British males and examined the 5'- and 3'-flanking regions in 20 out of these obese subjects. We also sequenced all these regions in 10 lean (BMI < 18 kg/m2) white British males for a reference. We identified a single nucleotide substitution that replaces valine with isoleucine at codon 103, in two obese subjects in the heterozygous state. No other nucleotide alterations were found. The prevalence of this missense variant was studied in 322 white British males (190 with BMI > 28 kg/m2 and 132 with BMI < 22 kg/m2) selected from a population-based epidemiological survey. In these subjects, no homozygotes for the isoleucine allele were found. The frequency of heterozygotes was similar (4.2 vs 4.5%) in the two groups and there was no significant difference in BMI, total skinfold thickness, plasma insulin and glucose levels between heterozygotes and codon-103 valine homozygotes in either group. These results suggest that coding sequence mutations in the MC-4 receptor gene are unlikely to be a major cause of human obesity, at least in white British males.

Adult↗

PubMed2006

A model to infer the pathogenic significance of CDH1 germline missense variants.

Germline mutations of the E-cadherin gene (CDH1) are involved in the tumorigenesis of hereditary diffuse gastric cancer (HDGC). Recent studies have highlighted the lifesaving potential of total prophylactic gastrectomy for CDH1 germline mutation carriers. In this regard, CDH1 germline mutations of the missense type represent a clinical burden in genetic counseling, as their pathogenic relevance is not straightforward. In this work, we have outlined a possible multivariate approach to infer the significance of such variants. We reviewed all HDGC-associated E-cadherin germline missense mutations reported to date. The information collected included: co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, and functional in vitro and in silico data. We used the neighbor-joining method to group mutations according to the collected information and assessed the robustness of mutation clusters with a bootstrap test. CDH1 germline missense variants were classified according to the parameters defined in the multivariate analysis. This analysis allowed the distribution of the variants into two distinct groups: neutral variants vs mutations. The model described in this study provides an important tool that can ultimately improve the genetic counseling offered to the carriers of the germline CDH1 missense variants.

Alleles↗

PubMed2004

The effects of BRCA1 missense variants V1804D and M1628T on transcriptional activity.

Many families with multiple cases of ovarian cancer, breast cancer, or both segregate inherited mutations in one allele of the tumor suppressor gene BRCA1. Genetic testing is used to assess cancer risk; however, testing can detect missense DNA alterations, called unclassified variants, of unknown functional and biological significance with uncertain risk implications. Some missense variants at the transcriptional activation domain of BRCA1 of cancer patients inactivate transcriptional activity of BRCA1, providing evidence that they are deleterious. We identified the variants V1804D and M1628T at the transcriptional activation domain of BRCA1 of two ovarian cancer patients without a family history of ovarian or breast cancer. To test if these residues are critical for transcriptional activation, we created V1804D and M1628T independently in BRCA1 cDNA via site-directed mutagenesis in a mammalian expression vector, pcDNA3.1. Wild-type, mutant, and empty vector constructs were tested in human kidney 293 cells using a p53-responsive luciferase reporter. M1628T had the same transcriptional activity as wild-type BRCA1 but V1804D and the empty vector control showed a 60% reduction. This indicates that V1804D is deleterious but M1628T is not.

Amino Acid Substitution↗

PubMed2001

Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant inherited disease caused by defects in the process of DNA mismatch repair (MMR), and mutations in the hMLH1 or hMSH2 genes are responsible for the majority of HNPCC. In addition to clear loss-of-function mutations conferred by nonsense or frameshift alterations in the coding sequence or by splice variants, genetic screening has revealed a large number of missense codons with less obvious functional consequences. The ability to discriminate between a loss-of-function mutation and a silent polymorphism is important for genetic testing for inherited diseases like HNPCC where the opportunity exists for early diagnosis and preventive intervention. In this study, quantitative in vivo DNA MMR assays in the yeast Saccharomyces cerevisiae were performed to determine the functional significance of amino acid replacements observed in the human population. Missense codons previously observed in human genes were introduced at the homologous residue in the yeast MLH1 or MSH2 genes. This study also demonstrated feasibility of constructing genes that encode functional hybrid human-yeast MLH1 proteins. Three classes of missense codons were found: (i) complete loss of function, i.e. mutations; (ii) variants indistinguishable from wild-type protein, i.e. silent polymorphisms; and (iii) functional variants which support MMR at reduced efficiency, i.e. efficiency polymorphisms. There was a good correlation between the functional results in yeast and available human clinical data regarding penetrance of the missense codon. The results reported here raise the intriguing possibility that differences in the efficiency of DNA MMR exist between individuals in the human population due to common polymorphisms.

Adaptor Proteins, Signal Transducing↗

PubMed2025

Decoding missense variants pleiotropy in the immune GPCR P2RY8.

G protein-coupled receptors (GPCRs) form the largest family of cell surface receptors and remain a central focus in pharmacology and drug discovery. Despite extensive structural and pharmacological studies, the functional impact of missense variation across GPCRs remains poorly understood, particularly for receptors involved in immune regulation. In this issue of Cell Genomics, LaFlam et al.1 systematically map P2RY8 variant functions using deep mutational scanning (DMS) combined with structural biology approaches, revealing pleiotropy and mechanisms linking GPCR variation to B cell confinement and lymphoma.

Humans↗

PubMed2026

A CCNA1 Missense Variant Associated With Chromatid Non-Disjunction in Abnormal-Headed Sperm and Male Infertility.

BACKGROUND: Macrozoospermia is a rare form of teratozoospermia characterized by tetraploids, large-headed spermatozoa with multiple flagella, usually caused by bi-allelic AURKC mutations. The etiology of atypical phenotypes with a lower proportion of large headed spermatozoa and single flagella however often remains unresolved. OBJECTIVE: To investigate the genetic cause of severe sperm-head abnormalities with moderate macrozoospermia without multiflagellated spermatozoa in a patient with repeated ICSI failure. An infertile male with three failed ICSI attempts underwent semen analysis, revealing complete teratozoospermia, including 25% macrocephalic spermatozoa. METHODS: Multi-probe FISH targeting chromosomes 13, 18, 21, X, Y assessed chromosomal segregation. Whole-exome sequencing (WES) was performed to identify a candidate variant associated with meiotic abnormalities. RESULTS: FISH analysis revealed a high proportion of spermatozoa with n (23) chromosomes and 2c DNA content, consistent with sister chromatid non-disjunction during meiosis II. WES identified a homozygous missense variation in CCNA1, coding for a protein described to be essential for meiotic progression and chromatin remodeling in male germ cells. DISCUSSION: The variant affects a highly conserved residue within a functional domain and is predicted to be deleterious. This study establishes the first clinical association between CCNA1 mutations and chromatid non-disjunction in human spermatogenesis. It highlights the limitations of current morphology-based diagnostic thresholds and supports cytogenetic and genomic assessment for severe teratozoospermia (especially head abnormalities) and ART failure. CONCLUSION: Expanding genetic screening panels to include CCNA1 may improve diagnostic precision and clinical management in atypical macrozoospermia cases.

ART failure↗

PubMed2005

A common missense variant in BRCA2 predisposes to early onset breast cancer.

INTRODUCTION: Mutations in the BRCA2 gene are one of the two major causes of hereditary breast cancer. Protein-truncating mutations of BRCA2 are usually deleterious and increase the risk of breast cancer up to 80% over a lifetime. A few missense mutations in BRCA2 are believed to have a similarly high penetrance, apart from more common neutral polymorphisms. It is often difficult to classify a particular sequence variant as a mutation or a polymorphism. For a deleterious variant, one would expect a greater allele frequency in breast cancer cases than in ethnic-matched controls. In contrast, neutral polymorphic variants should be equally frequent in the two groups. METHODS: We genotyped 3,241 cases of breast cancer diagnosed at under 51 years of age, unselected for family history, from 18 hospitals throughout Poland and 2,791 ethnic-matched controls for a single BRCA2 C5972T variant. RESULTS: The variant was present in approximately 6% of the Polish population. In the study, 13 women (11 cases and two controls (OR = 4.7; p = 0.02)) were homozygous for the variant allele. The overall odds ratio for breast cancer in women with a single copy of the BRCA2 C5972T variant was 1.1 (p = 0.7); however, the effect was significant for patients diagnosed at or before age 40 (OR = 1.4; p = 0.04). We reviewed the association between the BRCA2 variant in different histologic subgroups and found the effect most pronounced in women who had ductal carcinoma in situ (DCIS) with micro-invasion (OR = 2.8; p < 0.0001). CONCLUSION: The BRCA2 C5972T allele is a common variant in Poland that increases the risk of DCIS with micro-invasion. The homozygous state is rare but increases the risk of breast cancer five-fold.

Adult↗