Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein ...6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.
The aim of the study was to analyze frequency of
SHOX gene defects and selected dysmorphic signs in patients of both idiopathic short stature (ISS) and Léri–Weill dyschondrosteosis (LWD), all derived ...from the Czech population.
Overall, 98 subjects were analyzed in the study. Inclusion criteria were the presence of short stature (−
2.0 SD), in combination with at least one of the selected dysmorphic signs for the ISS
+
group; and the presence of Madelung deformity, without positive karyotyping for the LWD
+
group. Each proband was analyzed by use of P018 MLPA kit, which covers
SHOX and its regulatory sequences. Additionally, mutational analysis was done of the coding portions of the
SHOX.
Both extent and breakpoint localizations in the deletions/duplications found were quite variable. Some PAR1 rearrangements were detected, without obvious phenotypic association. In the ISS
+
group, MLPA analysis detected four PAR1 deletions associated with a
SHOX gene defect, PAR1 duplication with an ambiguous effect, and two
SHOX mutations (13.7%). In the LWD
+
group, MLPA analysis detected nine deletions in PAR1 region, with a deleterious effect on
SHOX, first reported case of isolated
SHOX enhancer duplication, and
SHOX mutation (68.8%). In both ISS
+
and LWD
+
groups were positivity associated with a disproportionately short stature; in the ISS
+
group, in combination with muscular hypertrophy.
It seems that small PAR1 rearrangements might be quite frequent in the population. Our study suggests disproportionateness, especially in combination with muscular hypertrophy, as relevant indicators of ISS to be the effect of
SHOX defect.
► We analyzed frequency of
SHOX defects and dysmorphic signs in ISS and LWD patients. ► Extent and breakpoint localizations were variable. ► Small PAR1 rearrangements might be quite frequent in the population. ► Disproportionateness with muscular hypertrophy indicates ISS results from
SHOX.
Inherited defects of skull ossification often manifest as symmetric parietal
foramina (PFM; MIM 168500). We previously identified mutations of MSX2
in non-syndromic PFM and demonstrated genetic ...heterogeneity.
Deletions of 11p11-p12 (proximal 11p deletion syndrome, P11pDS; MIM
601224; ref. 2) are characterized by multiple
exostoses, attributable to haploinsufficiency of EXT2 (refs. 3,4) and PFM. Here we identify
ALX4, which encodes a paired-related homeodomain transcription factor,
as the PFM disease gene in P11pDS.
Chondrodysplasia punctata represents clinically and genetically a heterogeneous group of disorders characterized by the presence of multiple congenital anomalies and stippled epiphyses. We present ...clinical course of the disease and the results of metabolic, X-ray and molecular analyses in 19-months old girl with X-linked dominant chondrodysplasia punctata with intrauterine growth retardation, craniofacial dysmorphy, cataracts, cutaneous anomalies including ichthyosis, asymmetric rhizomesomelic shortness of the limbs, deformity of the spine, club foot, polydactyly, syndactyly, epiphyseal stippling and low cholesterol (2.29 mmol/l). Spectrophotometric analysis revealed the presence of abnormal pattern of cholesterol precursors in blood. The increased level of 8-dehydrocholesterol (42.2 micromol/l, controls < 1) and 7-dehydrocholesterol (25.5 micromol/l, controls < 1) recognised with GC/MS suggested an endogenous defect of cholesterol biosynthesis. The diagnosis of X-linked dominant chondrodysplasia punctata (CDPX2) was confirmed by the molecular analysis. Sequencing of the EBP gene encoding for 3beta-hydroxysteroid-delta8,delta7-isomerase revealed the presence of "de novo" heterozygous mutation c.327C>T (p.Arg110Stop). High cholesterol diet normalized cholesterol level (3.28 mmol/l) but it had no influence on the unfavourable prognosis of the disease. Low level of cholesterol with abnormal sterol profile in a child with congenital development anomalies represent an important laboratory marker suggesting an inherited defect of cholesterol biosynthesis.
Case report describes successful prenatal diagnosis of skeletal dysplasia in the first trimester of pregnancy in a female patient affected with X-linked dominat chondrodysplasia punctata (CDPX2). Her ...first pregnancy was terminated in the second trimester due to skeletal dysplasia of the foetus. The diagnosis in the following pregnancy was finished in the first trimester - before the end of the 13th gestational week. The diagnosis was established on the basis of ultrasonographic (US) examination and mutation analysis of the EBP gene in the material of chorionic villus sampling (CVS).
Antley-Bixler syndrome (ABS) is a rare congenital disorder characterized by numerous craniofacial, skeletal and, in some cases, urogenital abnormalities resulting from disordered steroidogenesis. ...Known genetic causes in sporadic cases of ABS include dominant mutations in the fibroblast growth factor 2 receptor gene (FGFR2). Recent research shows surprisingly that symptoms of Antley-Bixler syndrome, combined with disordered steroidogenesis and urogenital anomalies, are caused by mutations in the POR gene that encodes NADPH-cytochrome P450 oxidoreductase (CYPOR). CYPOR is a four domain-containing monomeric flavoprotein that contains two flavins, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), a binding site for NADPH, and the N-terminal sequence of 25 amino acids which determines the microsomal localization of the protein. CYPOR is the electron donor to microsomally localized cytochromes P450 that participate in xenobiotic metabolism and steroidogenesis. Mutations in the POR gene lead to apparent diminished activity of some P450 enzymes. Association of CYPOR with ABS discloses new facts about this disease and recent research shows that patients with ABS-like skeletal anomalies, but with mutations in the POR gene and disordered steroidogenesis, represent a new disorder called POR deficiency.
To improve prenatal diagnostic with a feedback of autopsy, complemented by post mortem magnetic resonance imaging (MRI). MRI is important for malformations of CNS, where autopsy can be insufficient.
...Case report.
MR unit of the Department of radiology, Department of obstetrics and gynaecology and Department of pathology, 1st medical school, Charles University in Prague, General Teaching Hospital.
To compare prenatal ultrasound, post mortem MRI and autopsy.
Case report documented complementarity of all three method; full agreement in brain malformation type was found.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder, leading to end stage renal failure and kidney transplantation in its most serious form. The severity ...of the disease's manifestation depends on the genetic determination of ADPKD. The huge variability of different phenotypes (even within a single family) is not only modulated by the two main ADPKD genes (PKD1 and PKD2) but also by modifier genes and the whole genetic background.
This is a report of an ADPKD family with co-inheritance of PKD1 and PKD2 pathogenic variants. The proband, with an extremely serious manifestation of ADPKD (the man was diagnosed in early childhood, and with end stage renal disease aged 23), underwent genetic analysis of PKD1 and PKD2, which revealed the presence of pathogenic mutations in both of these genes. The missense PKD2 mutation p.Arg420Gly came from the proband's father, with a mild ADPKD phenotype. The same mutation of the PKD2 gene and similar mild disease presentation were found in the proband's aunt (father's sister) and her son. The nonsense mutation p.Gln2196* within the PKD1 gene was probably inherited from the proband's mother, who died at the age of 45. It was only discovered post mortem, that the real cause of her death was kidney failure as a consequence of untreated ADPKD. Unfortunately, neither the DNA of the proband's mother nor the DNA of any other family members from this side of the pedigree were available for further examination. The proband underwent successful cadaveric kidney transplantation at the age of 24, and this replacement therapy lasted for the next 15 years.
Here, we present a first case of bilineal ADPKD inheritance in the Czech Republic. This report highlights the significant role of modifier genes in genetic determination of ADPKD, especially in connection with seriously deteriorated disease phenotypes. In our case, the modifying role is probably mediated by the PKD2 gene.
This case report describes a finding of vascular malformation of an aborted foetus of gestational age of the 22nd week. This concerns meningocerebral angiodysplasia, located in the posterior fossa ...and around the thalami. This disease is rare and is often accompanied by renal agenesis. The finding was complicated by hydrocephalus. Our report compares all three diagnostic methods (prenatal ultrasonography, post-mortem MR and autopsy). Prenatal ultrasonography described only hydrocephalus and reduction of cerebral parenchyma. MR displayed the extent of the malformation, the exact diagnosis was however determined by histological examination. MR described agenesis of structures of midbrain, which was confirmed by autopsy.
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