Role of parental folate pathway single nucleotide polymorphisms in altering the susceptibility to neural tube defects in South India

Aim: To investigate the role of four parental folate pathway single nucleotide polymorphisms (SNPs) i.e., methylene tetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, methionine synthase reductase (MTRR) 66A>G and glutamate carboxypeptidase (GCP) II 1561C>T on susceptibility to neural tube defects (NTDs) in 50 couples with NTD offspring and 80 couples with normal pregnancy outcome. Results: Maternal MTHFR 677C→T (odds ratio (OR): 2.69, 95% confidence interval (CI): 1.35–5.34) and parental GCP II 1561C→T (maternal: OR: 1.89, 95% CI: 1.12–3.21 and paternal: OR: 3.23, 95% CI: 1.76–5.93) were found to be risk factors for a NTD. Both paternal and maternal GCP II T-variant alleles were found to interact with MTHFR 677T- and MTRR G-variant alleles in increasing the risk for NTD. Segregation of data based on type of defect revealed an association between maternal 677T-allele and meningomyelocele (OR: 9.00, 95% CI: 3.77–21.55, P<0.0001) and an association between parental GCP II 1561T-allele and anencephaly (maternal: OR: 2.25, 95% CI: 1.12–4.50, P<0.05 and paternal: OR: 4.26, 95% CI: 2.01–9.09, P<0.001). Conclusions: Maternal MTHFR C677T and parental GCP II C1561T polymorphisms are associated with increased risk for NTDs. Apart from individual genetic effects, epistatic interactions were also observed.Peer Reviewe

Autistic children exhibit distinct plasma amino acid profile

474-478In order to ascertain whether autistic children display characteristic metabolic signatures that are of diagnostic value, plasma amino acid analyses were carried out on a cohort of 138 autistic children and 138 normal controls using reverse-phase HPLC. Pre-column derivatization of amino acids with phenyl isothiocyanate forms phenyl thio-carbamate derivates that have a λmax of 254 nm, enabling their detection using photodiode array. Autistic children showed elevated levels of glutamic acid (120 <span style="font-family:Symbol; mso-ascii-font-family:" times="" new="" roman";mso-hansi-font-family:"times="" roman";="" letter-spacing:-.1pt;mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">± 89 vs. 83 ± 35 <span style="font-family: Symbol;mso-ascii-font-family:" times="" new="" roman";mso-hansi-font-family:"times="" roman";="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">mmol/L) and asparagine (85 <span style="font-family: Symbol;mso-ascii-font-family:" times="" new="" roman";mso-hansi-font-family:"times="" roman";="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">± 37 vs. 47 <span style="font-family:Symbol;mso-ascii-font-family: " times="" new="" roman";mso-hansi-font-family:"times="" roman";mso-char-type:symbol;="" mso-symbol-font-family:symbol"="" lang="EN-GB">± 19 mmol/L); lower levels of phenylalanine (45 ± 20 vs. 59 <span style="font-family:Symbol; mso-ascii-font-family:" times="" new="" roman";mso-hansi-font-family:"times="" roman";="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">± 18 mmol/L), tryptophan (24 <span style="font-family: Symbol;mso-ascii-font-family:" times="" new="" roman";mso-hansi-font-family:"times="" roman";="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">± 11 vs. 41 <span style="font-family:Symbol;mso-ascii-font-family: " times="" new="" roman";mso-hansi-font-family:"times="" roman";mso-char-type:symbol;="" mso-symbol-font-family:symbol"="" lang="EN-GB">± 16 mmol/L), methionine (22 <span style="font-family: Symbol;mso-ascii-font-family:" times="" new="" roman";mso-hansi-font-family:"times="" roman";="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">± 9 vs. 28 ± 9 <span style="font-family:Symbol;mso-ascii-font-family: " times="" new="" roman";mso-hansi-font-family:"times="" roman";mso-char-type:symbol;="" mso-symbol-font-family:symbol"="" lang="EN-GB">mmol/L) and histidine (45 ± 21 vs. 58 <span style="font-family:Symbol; mso-ascii-font-family:" times="" new="" roman";mso-hansi-font-family:"times="" roman";="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">± 15 mmol/L). A low molar ratio of (tryptophan/large neutral amino acids) × 100 was observed in autism (5.4 vs 9.2), indicating lesser availability of tryptophan for neurotransmitter serotonin synthesis. To conclude, elevated levels of excitatory amino acids (glutamate and asparagine), decreased essential amino acids (phenylalanine, tryptophan and methionine) and decreased precursors of neurotransmitters (tyrosine and tryptophan) are the distinct characteristics of plasma amino acid profile of autistic children. Thus, such metabolic signatures might be useful tools for early diagnosis of autism. </span

Expanding the Nude SCID/CID Phenotype Associated with FOXN1 Homozygous, Compound Heterozygous, or Heterozygous Mutations

Human nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with FOXN1 homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions

Mapping the NPHP-JBTS-MKS Protein Network Reveals Ciliopathy Disease Genes and Pathways

SummaryNephronophthisis (NPHP), Joubert (JBTS), and Meckel-Gruber (MKS) syndromes are autosomal-recessive ciliopathies presenting with cystic kidneys, retinal degeneration, and cerebellar/neural tube malformation. Whether defects in kidney, retinal, or neural disease primarily involve ciliary, Hedgehog, or cell polarity pathways remains unclear. Using high-confidence proteomics, we identified 850 interactors copurifying with nine NPHP/JBTS/MKS proteins and discovered three connected modules: “NPHP1-4-8” functioning at the apical surface, “NPHP5-6” at centrosomes, and “MKS” linked to Hedgehog signaling. Assays for ciliogenesis and epithelial morphogenesis in 3D renal cultures link renal cystic disease to apical organization defects, whereas ciliary and Hedgehog pathway defects lead to retinal or neural deficits. Using 38 interactors as candidates, linkage and sequencing analysis of 250 patients identified ATXN10 and TCTN2 as new NPHP-JBTS genes, and our Tctn2 mouse knockout shows neural tube and Hedgehog signaling defects. Our study further illustrates the power of linking proteomic networks and human genetics to uncover critical disease pathways