Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension

Table S5 RAD sequencing data set

RAD sequencing data set for 96 individuals from 10 populations of R. capensis from the Cape Floristic Region of South Africa

File S1 Pseudoreference part 1

Pseudoreference of concatenated unique RAD-seq clusters, separated by a stretch of five Ns, pseudochromosomes 1–6. Zip-compressed fasta file format

File S2 Pseudoreference part 2

Pseudoreference of concatenated unique RAD-seq clusters, separated by a stretch of five Ns, pseudochromosomes 7–12. Zip-compressed fasta file format

The role of prolactin in fish reproduction

Prolactin (PRL) has one of the broadest ranges of functions of any vertebrate hormone, and plays a critical role in regulating aspects of reproduction in widely divergent lineages. However, while PRL structure, mode of action and functions have been well-characterised in mammals, studies of other vertebrate lineages remain incomplete. As the most diverse group of vertebrates, fish offer a particularly valuable model system for the study of the evolution of reproductive endocrine function. Here, we review the current state of knowledge on the role of prolactin in fish reproduction, which extends to migration, reproductive development and cycling, brood care behaviour, pregnancy, and nutrient provisioning to young. We also highlight significant gaps in knowledge and advocate a specific bidirectional research methodology including both observational and manipulative experiments. Focusing research efforts towards the thorough characterisation of a restricted number of reproductively diverse fish models will help to provide the foundation necessary for a more explicitly evolutionary analysis of PRL function