Adult-onset neuronal ceroid lipofuscinoses (ANCL, Kufs disease) are rare hereditary neuropsychiatric disorders characterized by intralysosomal accumulation of ceroid in tissues. The ceroid accumulation primarily affects the brain, leading to neuronal loss and progressive neurodegeneration. Although several causative genes have been identified (DNAJC5, CLN6, CTSF, GRN, CLN1, CLN5, ATP13A2), the genetic underpinnings of ANCL in some families remain unknown. Here we report one family with autosomal dominant (AD) Kufs disease caused by a 30 bp in-frame duplication in DNAJC5, encoding the cysteine-string protein alpha (CSPα). This variant leads to a duplication of the central core motif of the cysteine-string domain of CSPα and affects palmitoylation-dependent CSPα sorting in cultured neuronal cells similarly to two previously described CSPα variants, p.(Leu115Arg) and p.(Leu116del). Interestingly, the duplication was not detected initially by standard Sanger sequencing due to a preferential PCR amplification of the shorter wild-type allele and allelic dropout of the mutated DNAJC5 allele. It was also missed by subsequent whole-exome sequencing (WES). Its identification was facilitated by reanalysis of original WES data and modification of the PCR and Sanger sequencing protocols. Independently occurring variants in the genomic sequence of DNAJC5 encoding the cysteine-string domain of CSPα suggest that this region may be more prone to DNA replication errors and that insertions or duplications within this domain should be considered in unsolved ANCL cases.

• MeSH
• buněčné linie MeSH
• dospělí MeSH
• duplikace genu * MeSH
• falešně negativní reakce MeSH
• genetické testování normy   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• myši MeSH
• neuronální ceroidlipofuscinózy genetika   patologie   MeSH
• neurony metabolismus   MeSH
• posttranslační úpravy proteinů MeSH
• proteiny tepelného šoku HSP40 genetika   metabolismus   MeSH
• sekvenování celého genomu normy   MeSH
• transport proteinů MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cysteine string protein MeSH Prohlížeč
• membránové proteiny MeSH
• proteiny tepelného šoku HSP40 MeSH

OBJECTIVE: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery. METHODS: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL. RESULTS: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis. CONCLUSIONS: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes.

• MeSH
• chybná diagnóza * MeSH
• dospělí MeSH
• lidé MeSH
• lipofuscin metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neuronální ceroidlipofuscinózy klasifikace   diagnóza   genetika   metabolismus   MeSH
• neurony metabolismus   ultrastruktura   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• lipofuscin MeSH

The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. We studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations (c.262C>T [p.Arg88*] and c.505C>T [p.Arg169*]) or splicing mutations (c.1435-12A>G [p.Gly479Phefs*119]) in ANTXR1, which encodes anthrax toxin receptor 1. The nonsense mutations predictably trigger nonsense-mediated mRNA decay, resulting in the loss of ANTXR1. The transcript with the splicing mutation theoretically encodes a truncated ANTXR1 containing a neopeptide composed of 118 unique amino acids in its C terminus. GAPO syndrome's major phenotypic features, which include dental abnormalities and the accumulation of extracellular matrix, recapitulate those found in Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix regulation. Thus, we propose that mutations affecting ANTXR1 function are responsible for this disease's characteristic generalized defect in extracellular-matrix homeostasis.

• MeSH
• alopecie genetika   patologie   MeSH
• alternativní sestřih genetika   MeSH
• anodoncie genetika   patologie   MeSH
• dědičné atrofie optického nervu genetika   patologie   MeSH
• DNA primery genetika   MeSH
• extracelulární matrix genetika   metabolismus   MeSH
• fibroblasty MeSH
• fluorescenční protilátková technika MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci genetika   MeSH
• homeostáza genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 2 genetika   MeSH
• mikrofilamentové proteiny MeSH
• místa sestřihu RNA genetika   MeSH
• molekulární sekvence - údaje MeSH
• nádorové proteiny genetika   MeSH
• nesmyslný kodon genetika   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• poruchy růstu genetika   patologie   MeSH
• receptory buněčného povrchu genetika   MeSH
• rodokmen MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza DNA MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• ANTXR1 protein, human MeSH Prohlížeč
• DNA primery MeSH
• mikrofilamentové proteiny MeSH
• místa sestřihu RNA MeSH
• nádorové proteiny MeSH
• nesmyslný kodon MeSH
• receptory buněčného povrchu MeSH