A novel PCFT gene mutation (p.Cys66LeufsX99) causing hereditary folate malabsorption

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder which is characterized by impaired intestinal folate malabsorption and impaired folate transport into the central nervous system. Mutations in the intestinal folate transporter PCFT have been reported previously in only 10 individuals with this disorder. The purpose of the current study was to describe the clinical phenotype and determine the molecular basis for this disorder in a family with four affected individuals. A consanguineous family of Pakistani origin with autosomal recessive HFM was ascertained and clinically phenotyped. After genetic linkage studies all coding exons of the PCFT gene were screened for mutations by direct sequencing. The clinical phenotype of four affected patients is described. Direct sequencing of PCFT revealed a novel homozygous frameshift mutation (c.194dupG) at a mononucleotide repeat in exon 1 predicted to result in a truncated protein (p.Cys66LeufsX99). This report extends current knowledge on the phenotypic manifestations of HFM and the PCFT mutation spectrum

Germline Mutation in NLRP2 (NALP2) in a Familial Imprinting Disorder (Beckwith-Wiedemann Syndrome)

Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans

Initiation codon mutation in βB1-crystallin (CRYBB1) associated with autosomal recessive nuclear pulverulent cataract

PurposeTo identify the molecular basis for autosomal recessively inherited congenital non-syndromic pulverulent cataracts in a consanguineous family with four affected children.MethodsAn autozygosity mapping strategy using high density SNP microarrays and microsatellite markers was employed to detect regions of homozygosity. Subsequently good candidate genes were screened for mutations by direct sequencing.ResultsThe SNP microarray data demonstrated a 24.96 Mb region of homozygosity at 22q11.21-22q13.2 which was confirmed by microsatellite marker analysis. The candidate target region contained the beta-crystallin gene cluster and direct sequencing in affected family members revealed a novel mutation in CRYBB1 (c.2T>A; p.Met1Lys).ConclusionsTo our knowledge this is the first case of an initiation codon mutation in a human crystallin gene, and only the second report of a CRYBB1 mutation associated with autosomal recessive congenital cataracts. In addition, although a number of genetic causes of autosomal dominant pulverulent cataracts have been identified (including CRYBB1) this is the first gene to have been implicated in autosomal recessive nuclear pulverulent cataract

A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease.

Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Δ 4-3-oxosteroid 5β-reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Mutations in SLC29A3, Encoding an Equilibrative Nucleoside Transporter ENT3, Cause a Familial Histiocytosis Syndrome (Faisalabad Histiocytosis) and Familial Rosai-Dorfman Disease

The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder