Neurodegenerative Genetics: The underlying genetics of neurodegenerative disorders tend not to be well understood. Novarino et al. (p. 506 ; see the Perspective by Singleton ) investigated the underlying genetics of hereditary spastic paraplegia (HSP), a human neurodegenerative disease, by sequencing the exomes of individuals with recessive neurological disorders. Loss-of-function gene mutations in both novel genes and genes previously implicated for this condition were identified, and several were functionally validated.

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease‐causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N‐terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist. Hum Mutat 31:992–1002, 2010.

Andrew Jackson, Peter Nürnberg and colleagues identify mutations in PLK4 and TUBGCP6 in individuals with microcephaly, primordial dwarfism, retinopathy and other congenital anomalies. These findings extend the spectrum of human phenotypes associated with centriole dysfunction. Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.

Osteogenesis imperfecta (OI) is characterized by susceptibility to bone fractures, with a severity ranging from subtle increase in fracture frequency to prenatal fractures. The first scientific description of OI dates from 1788. Since then, important milestones in OI research and treatment have, among others, been the classification of OI into 4 types (the ‘Sillence classification’), the discovery of defects in collagen type I biosynthesis as a cause of most cases of OI and the use of bisphosphonate therapy. Furthermore, in the past 5 years, it has become clear that OI comprises a group of heterogeneous disorders, with an estimated 90% of cases due to a causative variant in the COL1A1 or COL1A2 genes and with the remaining 10% due to causative recessive variants in the 8 genes known so far, or in other currently unknown genes. This review aims to highlight the current knowledge around the history, epidemiology, pathogenesis, clinical/radiological features, management, and future prospects of OI. The text will be illustrated with clinical descriptions, including radiographs and, where possible, photographs of patients with OI.