Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal disorder characterized by adult-onset cortical tremor and generalized seizures. Using whole genome sequencing, Yeetong et al. identify the causative mutation for type 4 of the disorder (BAFME4), providing insights into the underlying pathogenesis.

Benign Adult Familial Myoclonic Epilepsy (BAFME) is an autosomal dominant disorder characterized by adult-onset cortical tremor or action myoclonus predominantly in the upper limbs, and generalized seizures. We investigated a Thai BAFME family. Clinical and electrophysiological studies revealed that 13 were affected with BAFME. There were a total of 24 individuals studied. Genetic analysis by genome-wide linkage study (GWLS) was performed using 400 microsatellite markers and excluded linkage of the previous BAFME loci, 8q23.3-q24.1, and 2p11.1-q12.2. GWLS showed that the disease-associated region in our Thai family was linked to a newly identified locus on chromosome 3q26.32-3q28. This locus represents the fourth chromosomal region for BAFME.

Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Member 6 (KIF6) gene in a child displaying neurodevelopmental defects and intellectual disability. To test the pathogenicity of this novel human KIF6 mutation we engineered an analogous C-terminal truncating mutation in mouse. These mutant mice display severe, postnatal-onset hydrocephalus. We generated a Kif6-LacZ transgenic mouse strain and report expression specifically and uniquely within the ependymal cells (ECs) of the brain, without labeling other multiciliated mouse tissues. Analysis of Kif6 mutant mice with scanning electron microscopy (SEM) and immunofluorescence (IF) revealed specific defects in the formation of EC cilia, without obvious effect of cilia of other multiciliated tissues. Dilation of the ventricular system and defects in the formation of EC cilia were also observed in adult kif6 mutant zebrafish. Finally, we report Kif6-GFP localization at the axoneme and basal bodies of multi-ciliated cells (MCCs) of the mucociliary Xenopus epidermis. Overall, this work describes the first clinically-defined KIF6 homozygous null mutation in human and defines KIF6 as a conserved mediator of neurological development with a specific role for EC ciliogenesis in vertebrates.

No abstract

Benign adult familial myoclonic epilepsy type 1 (BAFME1) in several Japanese and Chinese families has recently been found to be caused by pentanucleotide repeat expansions in SAMD12. We identified a Thai family with six members affected with BAFME. Microsatellite studies suggested a linkage to the BAFME1 region on chromosome 8q24. Subsequently, longread whole-genome sequencing showed the (TTTTA) 446 (TTTCA) 149 in intron 4 of SAMD12 in an affected member. Repeatprimed PCR and long-range PCR revealed that the pentanucleotide repeat expansions segregated with the disease status. Our Thai family is the first non-Japanese and non-Chinese family with BAFME1. SNP array showed that the aberrant repeats had the same haplotype as those previously determined in Japanese and Chinese patients suggesting a common ancestry. The variant is estimated to arise ~12,000 years ago.

Background: Familial comedones without dyskeratosis are a rare autosomal dominant skin disorder, characterized by the occurrence of comedones that are distributed all over the body with specific features. We have previously reported two Thai families with familial comedones with expanded phenotypic spectrum. However, its genetic defect and pathogenesis remain unknown. Objective: To explore the molecular defect causing familial comedones. Methods: Whole-genome linkage analysis and whole-exome sequencing in family I were performed. Results: We identified a heterozygous one-base pair insertion, c.84_85insT (p. L28FfsX93) in PEN-2, located within the linked region on chromosome 19. PCR-Sanger sequencing confirmed the identified mutation. The mutation segregated with the disease phenotype in family I and was fully penetrant. This similar mutation was also present in the unrelated affected individual from family II. Quantitative PCR revealed increased mRNA expression of PEN-2 in leukocytes of affected individuals. Conclusion: We for the first time identify PEN-2 as the causative gene of familial comedones.

Van der Woude syndrome (VWS) is a dominantly inherited disorder characterized by cleft lip with or without cleft palate and lip pits. It remains the most common syndromic form of oral clefts. Mutations in the interferon regulatory factor 6 (IRF6) gene have been identified in patients with VWS. We reported three unrelated families with lower lip anomalies. Two had lower lip pits, a cardinal sign of VWS, but the other had a heart-shaped mass on lower lip without pits, oral clefts, or hypodontia. This isolated anomaly has not been previously observed in VWS. We performed mutation analysis by PCR-sequencing the entire coding region of the IRF6 gene. Three potentially pathogenic mutations, c.145C>T (p.Q49X), c.171T>G (p.F57L), and 1306C>G (p.L436V) were successfully identified. All the missense mutations were not detected in 100 unaffected ethnic-matched control chromosomes and have never been previously reported. The p.Q49X and p.F57L mutations were located in the highly conserved DNA binding domain while the p.L436V was located at the carboxy-terminal region. This study reported an undescribed clinical feature of VWS and three novel mutations, expanding the phenotypic spectrum of VWS and mutational spectrum of IRF6.