Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases.

BACKGROUND-Brain-derived neurotrophic factor (BDNF) has been found to be important in energy homeostasis in animal models, but little is known about its role in energy balance in humans. Heterozygous, variably sized, contiguous gene deletions causing haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13, approximately 4 Mb centromeric to BDNF (11p14.1), result in the Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome. Hyperphagia and obesity were observed in a subgroup of patients with the WAGR syndrome. We hypothesized that the subphenotype of obesity in the WAGR syndrome is attributable to deletions that induce haploinsufficiency of BDNF.

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Holoprosencephaly (HPE) is the most common malformation of the human forebrain, and may be due to cytogenetic anomalies, teratogens, occur in the context of a syndrome, or be due to mutations in single genes associated with non-syndromic HPE. Mutations in ZIC2, a transcription factor located on chromosome 13q32, are the second-most common cause of non-syndromic, non-chromosomal HPE. Blood samples from over 1000 individuals with HPE-spectrum disorders and their relatives were analyzed for sequence variations in ZIC2. We examined clinical details and included all other known previously published and unpublished cases of mutations in ZIC2 through a literature search and collaboration with other centers. We find mutations in ZIC2 in 8% of probands with HPE, and describe 153 individuals from 116 unrelated kindreds, including 137 patients with molecularly-determined mutations in ZIC2 and 16 patients with deletions of the ZIC2 locus. Unlike HPE due to mutations in other genes, the vast majority of cases are sporadic and the proportional distribution of HPE types differs significantly from previously published analyses of non-chromosomal non-syndromic HPE. Furthermore, we describe a novel facial phenotype in patients with mutations in ZIC2 which includes bitemporal narrowing, upsplanting palpebral fissures, a short nose with anteverted nares, and a broad and well-demarcated philtrum, and large ears. This phenotype is distinct from the standard facial dysmorphisms associated with non-chromosomal, non-syndromic HPE. Our findings show that HPE due to mutations in ZIC2 is distinct from that due to mutations in other genes. This may shed light on the mechanisms that contribute to the formation of the face and the forebrain and may help direct genetic counseling and diagnostic strategies.

Abnormalities of embryonic patterning are hypothesized to underlie many common congenital malformations in humans including congenital heart defects (CHDs), left-right disturbances (L-R) or laterality, and holoprosencephaly (HPE). Studies in model organisms suggest that Nodal-like factors provide instructions for key aspects of body axis and germ layer patterning; however, the complex genetics of pathogenic gene variant(s) in humans are poorly understood. Here we report our studies of FOXH1, CFC1, and SMAD2 and summarize our mutational analysis of three additional components in the human NODAL-signaling pathway: NODAL, GDF1, and TDGF1. We identify functionally abnormal gene products throughout the pathway that are clearly associated with CHD, laterality, and HPE. Abnormal gene products are most commonly detected in patients within a narrow spectrum of isolated conotruncal heart defects (minimum 5%-10% of subjects), and far less commonly in isolated laterality or HPE patients (approximately 1% for each). The difference in the mutation incidence between these groups is highly significant. We show that apparent gene dosage discrepancies between humans and model organisms can be reconciled by considering a broader combination of sequence variants. Our studies confirm that (1) the genetic vulnerabilities inferred from model organisms with defects in Nodal signaling are indeed analogous to humans; (2) the molecular analysis of an entire signaling pathway is more complete and robust than that of individual genes and presages future studies by whole-genome analysis; and (3) a functional genomics approach is essential to fully appreciate the complex genetic interactions necessary to produce these effects in humans.

Background Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. Objective To characterise genetic and clinical findings in patients with SIX3 mutations. Methods Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. Results In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. Conclusions Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype–phenotype correlation, as shown by functional studies using animal models.

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling.

Mutations within either the SHH gene or its related pathway components are the most common, and best understood, pathogenetic changes observed in holoprosencephaly patients; this fact is consistent with the essential functions of this gene during forebrain development and patterning. Here we summarize the nature and types of deleterious sequence alterations among over one hundred distinct mutations in the SHH gene (64 novel mutations) and compare these to over a dozen mutations in disease-related Hedgehog family members IHH and DHH. This combined structural analysis suggests that dysfunction of Hedgehog signaling in human forebrain development can occur through truncations or major structural changes to the signaling domain, SHH-N, as well as due to defects in the processing of the mature ligand from its pre-pro-precursor or defective post-translation bi-lipid modifications with palmitate and cholesterol